JP2001501936A - Vitronectin receptor antagonist - Google Patents

Abstract

  (57) [Summary] Disclosed are compounds that have a benzodiazepinyl core structure and are vitronectin receptor antagonists that are useful in treating osteoporosis, angiogenesis, tumor growth and metastasis, atherosclerosis, restenosis and inflammation.

Description

DETAILED DESCRIPTION OF THE INVENTION                     Vitronectin receptor antagonist                                Field of the invention   The present invention inhibits vitronectin receptors, inflammation, cancer and cardiovascular disorders, For example, atherosclerosis and restenosis, and diseases caused by bone resorption, For example, it relates to pharmaceutically active compounds useful for treating osteoporosis.                                Background of the Invention   Integrin is a transmembrane glycoprotein expressed in various cells A superfamily of cell-adsorbing receptors. These cell surface absorptions Adherent receptors are gpIIb / IIIa (fibrinogen receptor) and α_v β_Three(Vitronectin receptor). Fibrinogen receptor g pIIb / IIIa is expressed on the platelet surface and stops bleeding at the site of bleeding injury via platelet aggregation Form a clot (Philips et al., Blood., 1988, 71, 831). Vitronectin Scepter α_vβ_ThreeIs a variety of cells, including endothelium, smooth muscle, osteoclasts and tumor cells. It is expressed in the vesicle, and thus the receptor has various functions. Departs from the osteoclast membrane Α_vβ_ThreeThe receptor is a key step in the bone resorption process, the bone matrix of osteoclasts. Mediates adsorption to Rix (Ross et al., J. Biol. Chem., 1987, 262, 7703). Excessive A disease characterized by a degree of bone resorption is osteoporosis. Human aortic smooth muscle cells Α expressed in_vβ_ThreeReceptor causes restenosis after percutaneous coronary angioplasty Mediates its translocation into the neointima, a process known to occur (Brown et al., Cardiovascula r Res., 1994, 28, 1818). In addition, Brooks et al. In Cell, 1994, 79, 1157 , Α_vβ_ThreeAntagonist induces apoptosis of angiogenic blood vessels, resulting in post-tumor Clarified that retirement could be promoted. Thus, it blocks the vitronectin receptor. Drugs that block will be useful in the treatment of diseases such as osteoporosis, restenosis and cancer.   The vitronectin receptor is now alpha_vβ₁, Α_vβ_FiveAnd α_vβ_FiveNamed Sa (Horton et al., Int. J. Exp. Pat. hol., 1990, 71, 741). α_vβ_ThreeIs fibrin, fibrinogen, laminin, Thrombospondin, vitronectin, von Willebrand factor, osteo It binds to a variety of ligands, including pontin and bone sialosporin I. α_vβ_Five Binds to vitronectin. Vitronectin receptor α_vβ_FiveIs in the microvessel It is known to be contained in a variety of cell types, including skin cells (Davis et al., J.C. ell. Biol., 1993, 51, 206) and its role in angiogenesis was confirmed (Brooks Et al., Science, 1994, 264, 569). This integrin is found in normal skin vessels Not expressed, but expressed in damaged human granulation tissue.   The vitronectin receptor is a tripeptide Arg-G1y-Asp (or RGD) It is known that it binds to bone matrix proteins that have bone marrow. Or Thus, Horton et al., In Exp. Cell Res., 1991, 195, 368, Peptide and anti-vitronectin receptor antibody (23C6) And inhibits the spread of cells by osteoclasts. In addition, Sato et al., J. Cell .Bio., 1990, 111, 1713, echistatin having an RGD sequence (echistat in), snake venom peptide is a potent inhibitor of bone resorption in tissue culture, Inhibits the attachment of the liposome to bone.   This time, certain compounds have α_vβ_ThreeAnd α_vβ_FiveA potent inhibitor of the receptor Was found. In particular, such compounds are better than fibrinogen receptors It is a potent inhibitor of the vitronectin receptor.                                Summary of the Invention   The present invention has a pharmacological activity of inhibiting the vitronectin receptor and is useful for inflammation, cancer and the like. And cardiovascular disorders such as atherosclerosis and restenosis, and bone resorption Compounds of formula (I) shown below useful in the treatment of diseases such as osteoporosis caused by recovery Offer things.   The present invention also provides a medicament comprising a compound of formula (I) and a pharmaceutically acceptable carrier. A drug composition is provided.   The invention also provides a method of treating a disease mediated by the vitronectin receptor. I do. In a specific embodiment, the compound of the invention is used for atherosclerosis, restenosis. Useful for the treatment of diseases caused by stenosis, inflammation, cancer and bone resorption, such as osteoporosis You.                                Detailed description   The present invention relates to vitronectin receptors rather than fibrinogen receptors. Novel compounds that are potent inhibitors. This novel compound has a nitrogen-containing substitution Group is on the aromatic 6-membered ring of benzazepine and the aliphatic substituent containing an acidic group is benzazepine It has a benzazepine nucleus on the 7-membered ring of azepine. The benzazepine ring system comprises Preferably, it interacts with the vitronectin receptor and the ring system also Direct the side chains of the substituents on the 6 and 7 membered ring to interact favorably with the It is thought to attach. About 12 to 14 intervening shares via the shortest intramolecular pathway The bond forms the acidic group of the aliphatic substituent of the 7-membered ring of benzazepine with the benzazepine Is preferably present between the nitrogens of the nitrogen-containing substituents in the aromatic six-membered ring.   The present invention provides a compound of formula (I): [Where,   R¹Is R⁷Or one or more R^TenOr R⁷Available unions AC which may be substituted with_0-4Alkyl, AC_2-4Alkenyl, AC_2-4 Alkynyl, AC_3-4Oxoalkenyl, AC_3-4Oxoalkynyl, AC_1-4 Aminoalkyl, AC_3-4Aminoalkenyl, AC_3-4Aminoalkynyl ;   A is H, C_3-6Cycloalkyl, Het or Ar;   R⁷Is -COR⁸, -COCR '_TwoR⁹, -C (S) R⁸, -S (O)_mOR ', -S (O)_mN R'R ", -PO (OR '), -PO (OR')_Two, -NO_TwoOr tetrazolyl;   R⁸Is independently -OR ', -NR'R ", -NR'SO_TwoR ', -NR'OR' Or -OCR '_TwoCO (O) R ';   R⁹Is -OR ', -CN, -S (O)_rR ', -S (O)_mNR '_Two, -C (O) R ', -C (O) NR '_TwoOr -CO_TwoR ';   R^TenIs H, halo, -OR¹¹, -CN, -NR'R¹¹, -NO_Two, -CF_Three, CF_ThreeS ( O)_r-, -CO_TwoR ', -CONR'_Two, AC_0-6Alkyl-, AC_1-6Oxoalkyl -, AC_2-6Alkenyl-, AC_2-6Alkynyl-, AC_0-6Alkyloxy-, A -C_0-6Alkylamino- or AC_0-6Alkyl-S (O)_r-   R¹¹Is R ', -C (O) R', -C (O) NR '_Two, -C (O) OR ', -S (O)_mR 'also Is -S (O)_mNR '_TwoIs;   R^TwoIs   W is-(CHR^g)_a-U- (CHR^g)_b-   U is absent or CO, CR^g _Two, C (= CR^g _Two), S (O)_k, O, NR^g, CR^g OR^g, CR^g(OR^k) CR^g _Two, CR^g _TwoCR^g(OR^k), C (O) CR^g _Two, CR^g _TwoC ( O), CONRⁱ, NRⁱCO, OC (O), C (O) O, C (S) O, OC (S), C (S ) NR^g, NR^gC (S), S (O)_TwoNR^g, NR^gS (O)_Two, N = N, NR^gNR^g, N R^gCR^g _Two, CR^g _TwoNR^g, CR^g _TwoO, OCR^g _Two, C≡C or CR^g= CR^gIn R;   G is NR^e, S or O;   R^gIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_0-6 Alkyl or Ar-C_0-6Alkyl;   R^kIs R^g, -C (O) R^gOr -C (O) OR^fIs;   RⁱIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_{0- 6} Alkyl, Ar-C_0-6Alkyl, or halogen, CN, NR^g _Two, OR^g, SR^g , CO_TwoR^gAnd CON (R^g)_TwoSubstituted by one to three groups selected from C_1-6Alkyl;   R^fIs H, C_1-6Alkyl or Ar-C_0-6Alkyl;   R^eIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl, C_3-7Shi Chloalkyl-C_0-6Alkyl or (CH_Two)_kCO_TwoR^gIs;   R^bAnd R^cIs independently H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_{0 -6} Alkyl or C_3-6Cycloalkyl-C_0-6Alkyl, halogen, CF_Three, OR^f , S (O)_kR^f, COR^f, NO_Two, N (R^f)_Two, CO (NR^f)_Two, CH_TwoN (R^f)_TwoIn Or R^bAnd R^cTogether, halogen, CF_Three, C_1-4Alkyl, OR^f, S (O)_kR^f, COR^f, CO_TwoR^f, OH, NO_Two, N (R^f)_Two, CO (NR^f)_Two , And CH_TwoN (R^f)_TwoMay be substituted with up to three substituents selected from A 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or Forming methylenedioxy,   Q¹, Q^Two, Q^ThreeAnd Q^FourIs independently N or C—R^yWhere Q¹ , Q^Two, Q^ThreeAnd Q^FourOnly one of them is N,   R 'is H, C_1-6Alkyl, Ar-C_0-6Alkyl or C_3-6Cycloalkyl-C_0-6 Alkyl,   R "is R ', -C (O) R' or -C (O) OR ',   R "'is H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl, or C_3-6Cycloalkyl-C_0-6Alkyl, halogen, CF_Three, OR^f, S (O)_kR^f, COR^f, NO_Two, N (R^f)_Two, CO (NR^f)_Two, CH_TwoN (R^f)_TwoAnd   R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two, -CF_Three, C F_ThreeS (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _TwoOr halo, -OR^g,- SR^g, -CN, -NR^gR ", -NO_Two, -CF_Three, R'S (O)_r-, -CO_TwoR^g, -COR^g Or -CONR^g _TwoC optionally substituted with_1-6Alkyl,   a is 0, 1 or 2;   b is 0, 1 or 2;   k is 0, 1 or 2;   m is 1 or 2,   r is 0, 1 or 2;   s is 0, 1 or 2;   u is 0 or 1;   v means 0 or 1] Or a pharmaceutically acceptable salt thereof.   Pharmaceutically acceptable addition salts and complexes of the compounds of the present invention are also included in the present invention. You. When the compound of the present invention has one or more chiral centers, Unless otherwise described, the present invention provides a single non-racemic compound that is conventionally synthesized and resolved. Include. When the compound has an unsaturated carbon-carbon double bond, cis (Z) And the trans (E) isomer are both within the scope of the present invention. If the compound is keto-e Nord In some cases, it may be present in equilibrium or substituted as appropriate with R ′ Each tautomeric form, fixed in one form, is considered to be included in the present invention. You.   Compounds of formula (I) are vitronectin and other RGD-containing peptides Inhibits binding to the cutin receptor. Vitronectin receptor on osteoclasts Inhibition of osteoclastic bone resorption inhibits bone resorption. Useful in the treatment of diseases such as osteoporosis and osteoarthritis.   Another embodiment of the present invention relates to a compound that results in increased osteocalcin release. Is a method for stimulating bone formation. Increased osteogenesis, mineralized bone Conditions in which the mass of the bone is deficient or in which bone remodeling is desirable, such as a fracture It is clear that there are benefits in healing and preventing fractures. The loss of bone structure The resulting disease and metabolic disorders will also benefit from such treatment. An example For example, hyperparathyroidism, Paget's disease, malignant hypercalcemia, Is bone metastasis due to sex hormone deficiency, osteolytic lesions induced by bone deficiency, For Jet's disease, osteomalacia, osteoprosthesis and osteopetrosis, the compounds of the invention may be administered. And you can benefit from it.   In addition, the compounds of the present invention may activate vitronectin receptors on many types of cells. To inhibit, the compounds are used in inflammatory disorders such as rheumatoid arthritis and psoriasis, And treatment of cardiovascular diseases such as atherosclerosis and restenosis Would be useful in The compounds of formula (I) of the present invention include, but are not limited to, blood Embolism disorders, asthma, allergies, adult respiratory distress syndrome, graft-versus-host disease, organs Graft rejection, septic shock, eczema, contact dermatitis, inflammatory bowel disease and other It may be useful for treating or preventing other diseases, including autoimmune diseases. Departure Ming compound also It is also useful for wound healing.   The compounds of the present invention are also useful for the treatment of angiogenic disorders, including prophylaxis. Book The term angiogenesis disorder as used herein encompasses conditions, including abnormal neovascularization. You. If the growth of new blood vessels is the cause of or is associated with the disease If so, inhibiting angiogenesis would reduce the deleterious effects of the disease U. One example of such a targeted disease is diabetic retinopathy. Support harmful tissue When the growth of new blood vessels is required, the inhibition of blood vessel formation The supply of fluid will decrease, and the tissue mass will decrease based on the blood supply. For example, in order for tumors to grow and to establish solid tumor metastases, Tumor growth that requires continuous angiogenesis. Thus, the compound of the present invention The thing inhibits tumor tissue angiogenesis, thereby preventing tumor metastasis and tumor growth.   Thus, according to the method of the present invention, the compounds of the present invention are used to inhibit angiogenesis. The symptoms of the disease would then be improved and, in some cases, the disease could be cured.   Another therapeutic target for compounds of the present invention is the eye characterized by angiogenesis Is a disease. Such eye diseases include corneal neovascular disorders, such as corneal transplants, blisters Eruptive keratitis, syphilitic keratitis, pterygium and neovascularization associated with contact lens use Sex pannus. Senile macular degeneration and estimated eye hiss as further eye diseases Includes toplasmosis, retinopathy of prematurity, and neovascular glaucoma.   The present invention further provides compounds of formula (I) and antitumor agents such as topotecan and Tumors that are given in a stepwise or physical combination with cisplatin and cisplatin Methods for inhibiting proliferation are provided.   With respect to formula (I),   Suitably, R^TwoIs Where Q¹, Q^TwoAnd Q^ThreeIs the CR^yAnd Q^FourIs CR^yOr N, u is 0, R 'is preferably each H, and R "is H, C_{1- 6} Alkyl, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl, -C (O) C_0-6A Lucyl-Ar or -C (O) OC_0-6Alkyl-Ar, W is -CH_Two-CH_Two-so Oh, R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two, -CF_Three , -CF_ThreeS (O)_r-, -CO_TwoR^g, -COR^g-CONR^g _TwoOr C_1-6Means alkyl To taste.   Also, R^TwoIs Where Q¹, Q^TwoAnd Q^ThreeAre each CH, u is 0, and Preferably, R 'is H or C, respectively._1-4R "is H or C_1-6A Where v is 0.   Also, R^TwoIs Where G is NH and R^bAnd R^cAre each H, preferably , W is -NR^g-(CHR^g)_b-Yes.   Also, R^TwoIs Where G is NH and R^bAnd R^cTogether, halogen, C_1-4Al Kill, OR^f, S (O)_kR^f, COR^f, CO_TwoR^f, OH, NO_Two, N (R^f)_Two, CO ( NR^f)_TwoAnd CH_TwoN (R^f)_TwoSubstituted with up to three substituents selected from A 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring or Chile Form dioxy. Preferably, R^bAnd R^cIs a 6-membered carbon ring together Or forms a heterocyclic ring, W is -CH_Two-CH_Two-Yes.   Also, R^TwoIsR ′ is H, and R ″ is H or C_1-4Alkyl, R^gIs H Or C_1-4Alkyl, wherein s is 0, 1 or 2, preferably W is- CH_Two-CH_Two-Yes.   With respect to formula (I), suitably R¹Is H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, -CH_TwoCF_Three,-( CH_Two)_1-2C (O) OR 'or-(CH_Two)_TwoOR '. Preferably, R¹Is H, C_1-4 Alkyl, Ph-C_1-4Alkyl, -CH_TwoCF_Three,-(CH_Two)_1-2C (O) OR ' Is-(CH_Two)_TwoOR 'where R' is H or C_1-4Alkyl. Most preferred Or R¹Is -CH_TwoCF_ThreeIt is.   Representative novel compounds of the present invention include the following:   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, 5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (4-Amino-2-pyridylamino) -1-propyloxy] -3-oxo -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (4-Methoxy-2-pyridylamino) -1-propyloxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -2-methyl-3-oxo -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (2-Imidazolylamino) -1-propyloxy] -3-oxo-2,3 , 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- [2- (1,4,5,6-tetrahydropyrimidinyl) amino] -1-pro Pyroxy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4 -vinegar acid;   (±) -8- [2- [6- (methylamino) pyridyl] ethoxy] -3-oxo-2,3,4,5 -Tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [2- (2-benzimidazolyl) ethoxy] -3-oxo-2,3,4,5-te Trahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [2- (4-aza-2-benzimidazolyl) ethoxy] -3-oxo-2,3, 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [2- (benzimidazol-2-yl) -1-ethoxy] -3-oxo-2,3, 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (4-Aminopyridin-2-ylamino) -1-propyloxy] -2- Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid ;   (±) -3-oxo-8- [3- (pyrimidin-2-ylamino) -1-propyloxy] -2 , 3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (R) -8- [3- (4-aminopyridin-2-ylamino) -1-propyloxy]- 3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3-[(1,4,5,6-tetrahydropyrimidin-2-yl) a Mino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine -4-acetic acid;   (S) -8- [3- (4-aminopyridin-2-ylamino) -1-propyloxy] -3- Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni L) amino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-acetic acid;   (±) -8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarboni L) amino] -1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H-2 -Benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( 4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-acetic acid;   (±) -2-Methyl-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (methyl) amido [No] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine -4-acetic acid;   (±) -2-benzyl-3-oxo-8- [3- (pyridin-2-ylamino) -1-propyl Oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -2- (carboxymethyl) -3-oxo-8- [3- (pyridin-2-ylamino)- 1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar acid;   (±) -2- (4-aminobenzyl) -3-oxo-8- [3- (pyridin-2-ylamino) -1-Proxyoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4- Acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (benzoyl) amino] 1- Propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahi Dro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (2-Imidazolin-2-ylamino) -1-propyloxy] -2-me Tyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzaze Pin-4-acetic acid;   (±) -8- [2- (2-Aminothiazol-4-yl) -1-ethoxy] -2-methyl-3-o Xo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (4,6-dimethylpyridin-2-ylamino) -1-propyloxy]- 2-Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar acid;   (±) -8- [3- (4,5,6,7-tetrahydro-1H-1,3-diazepin-2-ylua Mi No) -1-Propyloxy] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1H -2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butylacetyl) Amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4, 5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (isobutoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( 4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-acetic acid;   (±) -3-oxo-8- [3- (4-methylpyridin-2-ylamino) -1-propylthio [Xy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2- Benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (methyl) amino]]-1-p Propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahi Dro-1H-2-benzazepine-4-acetic acid;   (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzaze Pin-4-acetic acid;   (R) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzaze Pin-4-acetic acid;   (S) -8- [3- (4-Methylpyridin-2-ylamino) -1-propyloxy] -3-o Oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2- Benzazepine-4-acetic acid;   (S) -3-oxo-8- [3- (1,4,5,6-tetrahydropyrimid-2-ylamino) -1-propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-te Tiger Hydro-1H-2-benzazepine-4-acetic acid;   (S) -3-oxo-2- (2-phenylethyl) -8- [3- (pyridin-2-ylamino)- 1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar acid;   (S) -8- [2- [6- (methylamihapyridin-2-yl] -1-ethoxy] -3-oxo- 2- (2-phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine- 4-acetic acid;   (S) -8- [2- [6- (methylamihapyridin-2-yl] -1-ethoxy] -3-oxo- 2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benz Azepine-4-acetic acid; and   (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2- Benzazepine-4-acetic acid; Or a pharmaceutically acceptable salt thereof.   If the compounds of the present invention have one or more chiral centers, The present invention encompasses each single non-racemic compound that can be synthesized and resolved in a conventional manner. Include. According to the invention, the (S) configuration of the compound of formula (I) is preferred.   When the compound has an unsaturated carbon-carbon double bond, cis (Z) and Both isomers of lance (E) are within the scope of the present invention. In any case The meanings of the substituents have an independent meaning, and the same applies to other substituents.   Prodrugs of the compounds of the present invention are also included in the present invention. Prodrug is a carrier Is believed to release the active parent drug of formula (I) in vivo, It is. Thus, in another aspect of the present invention, a compound of formula (I) is prepared A novel prodrug, which is also an intermediate in the process, has the formula (II):[Where,   R¹Is R⁷Or one or more R^TenOr R⁷Available unions AC which may be substituted with_0-4Alkyl, AC_2-4Alkenyl, AC_2-4 Alkynyl, AC_3-4Oxoalkenyl, AC_3-4Oxoalkynyl, AC_1-4 Aminoalkyl, AC_3-4Aminoalkenyl, AC_3-4Aminoalkynyl ;   A is H, C_3-6Cycloalkyl, Het or Ar;   R⁷Is -COR⁸, -COCR '_TwoR⁹, -C (S) R⁸, -S (O)_mOR ', -S (O)_mN R'R ", -PO (OR '), -PO (OR')_Two, -NO_TwoOr tetrazolyl;   R⁸Is independently -OR ', -NR'R ", -NR'SO_TwoR ', -NR'OR' Or -OCR '_TwoCO (O) R ';   R⁹Is -OR ', -CN, -S (O)_rR ', -S (O)_mNR '_Two, -C (O) R ', -C (O) NR '_TwoOr -CO_TwoR ';   R^TenIs H, halo, -OR¹¹, -CN) -NR'R¹¹, -NO_Two, -CF_Three, CF_ThreeS ( O)_r-, -CO_TwoR ', -CONR'_Two, AC_0-6Alkyl-, AC_1-6Oxoalkyl -, AC_2-6Alkenyl-, AC_2-6Alkynyl-, AC_0-6Alkyloxy-, A -C_0-6Alkylamino- or AC_0-6Alkyl-S (O)_r-   R¹¹Is R ', -C (O) R', -C (O) NR '_Two, -C (O) OR ', -S (O)_mR 'also Is -S (O)_mNR '_TwoIs;   R^TwoIs Or   W is-(CHR^g)_a-U- (CHR^g)_b-   U is absent or CO, CR^g _Two, C (= CR^g _Two), S (O)_k, O, NR^g, CR^g OR^g, CR^g(OR^k) CR^g _Two, CR^g _TwoCR^g(OR^k), C (O) CR^g _Two, CR^g _TwoC ( O), CONRⁱ, NRⁱCO, OC (O), C (O) O, C (S) 0, OC (S), C (S ) NR^g, NR^gC (S), S (O)_TwoNR^g, NR^gS (O)_Two, N = N, NR^gNR^g, N R^gCR^g _Two, CR^g _TwoNR^g, CR^g _TwoO, OCR^g _Two, C≡C or CR^g= CR^gIn R;   G is NR^e, S or O;   R^gIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_0-6 Alkyl or Ar-C_0-6Alkyl;   R^kIs R^g, -C (O) R^gOr -C (O) OR^fIs;   RⁱIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_0-6 Alkyl, Ar-C_0-6Alkyl, or halogen, CN, NR^g _Two, OR^g, SR^g, CO_TwoR^gAnd CON (R^g)_TwoSubstituted by one to three groups selected from C_1-6Alkyl;   R^fIs H, C_1-6Alkyl or Ar-C_0-6Alkyl;   R^eIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl, C_3-7Shi Chloalkyl-C_0-6Alkyl or (CH_Two)_kCO_TwoR^gIs;   R^bAnd R^CIs independently H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_{O -6} Alkyl or C_3-6Cycloalkyl-C_0-6Alkyl, halogen, CF_Three, OR^f , S (O)_kR^f, COR^f, NO_Two, N (R^f)_Two, CO (NR^f)_Two, CH_TwoN (R^f)_Twoso Is or R^bAnd R^cTogether, halogen, CF_Three, C_1-4Alkyl , OR^f, S (O)_kR^f, COR^f, CO_TwoR^f, OH, NO_Two, N (R^f)_Two, CO (NR^f )_Two, And CH_TwoN (R^f)_TwoEven if substituted with up to three substituents selected from A good 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, Or form methylenedioxy,   Q¹, Q^Two, Q^ThreeAnd Q^FourIs independently N or C—R^yWhere Q¹ , Q^Two, Q^ThreeAnd Q^FourOnly one of them is N,   R 'is H, C_1-6Alkyl, Ar-C_0-6Alkyl or C_3-6Cycloalkyl-C_0-6 Alkyl,   R "is R ', -C (O) R' or -C (O) OR ',   R "'is H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl or C_3-6 Cycloalkyl-C_0-6Alkyl, halogen, CF_Three, OR^f, S (O)_kR^f, C OR^f, NO_Two, N (R^f)_Two, CO (NR^f)_Two, CH_TwoN (R^f)_TwoAnd   R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two, -CF_Three, C F_ThreeS (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _TwoOr halo, -OR^g,- SR^g, -CN, -NR^gR ", -NO_Two, -CF_Three, R'S (O)_r-, -CO_TwoR^g, -COR^g Or -CONR^g _TwoC optionally substituted with_1-6Alkyl,   a is 0, 1 or 2;   b is 0, 1 or 2;   k is 0, 1 or 2;   m is 1 or 2,   r is 0, 1 or 2;   s is 0, 1 or 2;   u is 0 or 1;   v means 0 or 1] Or a pharmaceutically acceptable salt thereof.   Representative examples of the novel prodrugs of the present invention are:   (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2, Methyl 3,4,5-tetrahydro-1H-2-benzazepine-4-acetate; and   (±) -8- [3- (4-Aminopyridin-2-ylamino) -1-propyloxy] -3-o Xo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-ethyl acetate;   Or a pharmaceutically acceptable salt thereof.   Yet another embodiment of the present invention relates to a compound of formula (III): [Where,   R¹Is R⁷Or one or more R^TenOr R⁷Available unions AC which may be substituted with_0-4Alkyl, AC_2-4Alkenyl, AC_2-4 Alkynyl, AC_3-4Oxoalkenyl, AC_3-4Oxoalkynyl, AC_1-4 Aminoalkyl, AC_3-4Aminoalkenyl, AC_3-4Aminoalkynyl ;   A is H, C_3-6Cycloalkyl, Het or Ar;   R⁷Is -COR⁸, -COCR '_TwoR⁹, -C (S) R⁸, -S (O)_mOR ', -S (O)_mN R'R ", -PO (OR '), -PO (OR')_Two, -NO_TwoOr tetrazolyl;   R⁸Is independently -OR ', -NR'R ", -NR'SO_TwoR ', -NR'OR' Or -OCR '_TwoCO (O) R ';   R⁹Is -OR ', -CN, -S (O)_rR ', -S (O)_mNR '_Two, -C (O) R ', -C (O) NR '_TwoOr -CO_TwoR ';   R^TenIs H, halo, -OR¹¹, -CN, -NR'R¹¹, -NO_Two, -CF_Three, CF_ThreeS ( O)_r-, -CO_TwoR ', -CONR'_Two, AC_0-6Alkyl-, AC_1-6Oxoalkyl -, AC_2-6Alkenyl-, AC_2-6Alkynyl-, AC_0-6Alkyloxy-, A -C_0-6Alkylamino- or AC_0-6Alkyl-S (O)_r-   R¹¹Is R ', -C (O) R', -C (O) NR '_Two, -C (O) OR ', -S (O)_mR 'also Is -S (O)_mNR '_TwoIs;   W is-(CHR^g)_a-U- (CHR^g)_b-   U is absent or CO, CR^g _Two, C (= CR^g _Two), S (O)_k, O, NR^g, CR^g OR^g, CR^g(OR^k) CR^g _Two, CR^g _TwoCR^g(OR^k), C (O) CR^g _Two, CR^g _TwoC ( O), CONRⁱ, NRⁱCO, OC (O), C (O) O, C (S) O, OC (S), C (S ) NR^g, NR^gC (S), S (O)_TwoNR^g, NR^gS (O)_Two, N = N, NR^gNR^g, N R^gCR^g _Two, CR^g _TwoNR^g, CR^g _TwoO, OCR^g _Two, C≡C or CR^g= CR^gIn R;   R^gIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_0-6 Alkyl or Ar-C_0-6Alkyl;   R^kIs R^g, -C (O) R^gOr -C (O) OR^fIs;   RⁱIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_0-6 Alkyl, Ar-C_0-6Alkyl, or halogen, CN, NR^g _Two, OR^g, SR^g, CO_TwoR^gAnd CON (R^g)_TwoSubstituted by one to three groups selected from C_1-6Alkyl;   R^fIs H, C_1-6Alkyl or Ar-C_0-6Alkyl;   Q¹, Q^Two, Q^ThreeAnd Q^FourIs independently N or C—R^yWhere Q¹ , Q^Two, Q^ThreeAnd Q^FourOnly one of them is N,   R 'is H, C_1-6Alkyl, Ar-C_0-6Alkyl or C_3-6Cycloalkyl-C_0-6 Alkyl,   R "is R ', -C (O) R' or -C (O) OR ',   R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two, -CF_Three, C F_ThreeS (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _TwoOr halo, -OR^g,- SR^g, -CN, -NR^gR ", -NO_Two, -CF_Three, R'S (O)_r-, -CO_TwoR^g, -COR^g Or -CONR^g _TwoC optionally substituted with_1-6Alkyl,   a is 0, 1 or 2;   b is 0, 1 or 2;   m is 1 or 2,   r represents 0, 1 or 2] Or a pharmaceutically acceptable salt thereof.   Abbreviations and symbols commonly used in the peptide and chemistry arts are Used to describe the compound of Generally, amino acid abbreviations are Eur.J.Biochem., 1 58, 9 (1984) IUPAC-IUB Joint on Biochemical Nomenclature Obey.   C used in this specification_1-4Alkyl is substituted with 1 to 4 carbon atoms Alkyl, which may be methyl, ethyl, n-propyl, isoprene, Includes propyl, n-butyl, isobutyl and t-butyl. C_1-6Alkyl Further includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl. Includes syl as well as its simple aliphatic isomers. C_0-4Alkyl and C_0-6A Alkyl further requires that the alkyl group need not be present (eg, Means).   C_1-4Alkyl or C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynil Or C_1-6An oxoalkyl is a group R^xMay be substituted with a stable structure And can be on any available carbon atom by conventional synthetic means. No. R^xA suitable group for is_1-4Alkyl, OR ', SR', C_1-4Alkyls Ruphonyl, C_1-4Alkylsulfoxyl, -CN, N (R ')_Two, CH_TwoN (R ')_Two, -N O_Two, -CF_Three, -CO_TwoR'-CON (R ')_Two, -COR ', -NR'C (O) R', F, Cl, Br, I or CF_ThreeS (O)_r-(Where r is 0, 1 or 2).   Halogen or halo means F, Cl, Br and I.   Ar or aryl as used herein is phenyl or naphthyl, or 1 to 3 substituents, such as those mentioned above for alkyl, especially_1-4 Alkyl, C_1-4Alkoxy, C_1-4Alkylthio, CF_Three, NH_Two, OH, F , Cl, Br or I means phenyl or naphthyl.   Het or heterocycles are stable and accessible by conventional chemical synthesis Containing one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. An optionally substituted 5- or 6-membered monocyclic ring, or 9- or 10-membered Refers to a bicyclic ring. Typical heterocycles are benzofuryl and benzimidazo , Benzopyran, benzothiophene, furan, imidazole, indoline, Morpholine, piperidine, piperazine, pyrrole, pyrrolidine, tetrahydropi Lysine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and Are tetra- and perhydro-quinolines and isoquinolines. For chemical synthesis More available and stable, such as the substituents described above for alkyl, Available combinations of up to three substituents on the Het ring are also within the scope of the invention. You.   C_3-7Cycloalkyl has 3 to 7 carbon atoms which may be substituted. And may have up to two unsaturated carbon-carbon bonds. Scripture Type C_3-7Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl , Cyclopentenyl, cyclohexyl, cyclohexenyl and cyclohepti It is. Alkyls available and stable through conventional chemical synthesis Any combination of up to three substituents on a cycloalkyl ring as described above. Combinations are also within the scope of the present invention.   R^bAnd R^cTogether, R^bAnd R^c5 fused to the ring to which When forming a 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, its form The ring formed is generally a 5- or 6-membered member selected from the rings described above for Het. Heterocyclyl or phenyl, cyclohexyl or cyclopentyl It is a ring. Preferably, R^bAnd R^cIs -D1 = D2-D3 = D4- Wherein D1 to D4 are independently CH, N or C—R_x; However, , D1 through D4 are N. R^bAnd R^cWhen together -CH = CH Most preferably, it forms a -CH = CH- group.   In this specification, certain types of radical groups are abbreviated. t-Bu is a tertiary butyl group , Boc refers to t-butyloxycarbonyl group, Fmoc refers to fluorenyl methoxy Ph refers to phenyl group, Cbz refers to benzyloxycarbonyl Bn refers to benzyl group, Me refers to methyl, Et refers to ethyl, Ac Means acetyl, Alk is C_1-4Refers to alkyl, Nph refers to 1- or 2-naphthyl CHex refers to cyclohexyl. Tet refers to 5-tetrazolyl.   In the present specification, certain reagents are abbreviated. DCC is dicyclohexylcarbo Diimide, DMAP refers to dimethylaminopyridine, DIEA refers to diiso Propylethylamine; EDC is 1- (3-dimethylaminopropyl) -3 -Refers to ethyl carbodiimide hydrochloride. HOBt is 1-hydroxybenzotria Sol, THF refers to tetrahydrofuran, DIEA refers to diisopropyl Ethyamine, DEAD means diethyl azodicarboxylate, PPh_ThreeIs bird Phenylphosphine, DIAD means diisopropyl azodicarboxylate , DME refers to dimethoxyethane, DMF refers to dimethylformamide, N BS refers to N-bromosuccinimide, Pd / C refers to palladium on carbon catalyst , PPA refers to polyphosphoric acid, DPPA refers to diphenylphosphoryl azide, BOP is benzotriazol-1-yloxytris (dimethylamino) phos Honium hexafluorophosphate, HF refers to hydrofluoric acid, TE A means triethylamine, TFA means trifluoroacetic acid, PCC means Refers to pyridinium lochromate.   Compounds of formula (I) generally have the formula (IV): With a compound of formula (V): R^Two-L¹Prepared by reacting with a compound of:   Where R¹And R^TwoIs the same as described in the formula (I), and the reactive functional group is Security Protected, L¹Is OH or halo.   Thereafter, the protecting group may be removed, if desired, to form a pharmaceutically acceptable salt.   Suitably, certain compounds of formula (I) have the formula (IV): Of the formula (VI): Prepared by reacting with the following compound:   Where R¹, R ', R ", W, Q¹, Q^Two, Q^ThreeAnd Q^FourIs the description of formula (I) Same, with the reactive functionality protected.   Thereafter, the protecting group may be removed, if desired, to form a pharmaceutically acceptable salt.   Preferably, for compounds of formula (VI), Q¹, Q^Two, Q^ThreeAnd Q^FourIs CH , W is -CH_Two-CH_Two-, R 'is H, R "is H, C_1-4Alkyl or -C (O) OC_1-4Alkyl. Suitably, a compound of formula (IV) and a compound of formula (VI) The reaction between the compounds is carried out in an aprotic solvent with diethyl azodicarboxylate and triphenylene. Performed in the presence of luphosphine.   In addition, certain compounds of formula (I) have the formula (IV): Of the formula (VII): Prepared by reacting with the compound of:   Where R¹, R ', R ", W, Q¹, Q^Two, Q^ThreeAnd v are the same as described in the formula (I). And the reactive functional groups are protected.   Thereafter, the protecting group may be removed, if desired, to form a pharmaceutically acceptable salt.   Preferably, for compounds of formula (VII), Q¹, Q^TwoAnd Q^ThreeIs CH and W Is -CH_Two-CH_Two-, V is 0, R 'is H, R "is H or C_1-4 Alkyl. Suitably, the reaction between a compound of formula (IV) and a compound of formula (VII) Is a mixture of diethyl azodicarboxylate and triphenylphosphine in an aprotic solvent. Perform in the presence of   Compounds of formula (I) are prepared by the general methods described in Schemes I-VII.Scheme I a) 2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide, DEAD , (Ph)_ThreeP, DMF; b) cyclohexene, 10% Pd / C, 2-propanol; c) 1.0N LiOH, THF, H_TwoO, then acidification   Compound I-1 (the preparation of which is described in Bondinell et al. (WO 93/000009)). Using the general procedure described), a Mitsunobu-type coupling reaction (Organic React ions 1992, 42, 335-656; Synthesis 1981, 1-28), 2-[(3-hydroxy-1-) Propyl) amino] pyridine-N-oxide to give 1-2. The reaction is a Due to the complex formed between diethyl zodicarboxylate and triphenylphosphine Mediated Aprotic solvents such as THF, CH_TwoCl_TwoOr done in DMF. I -2, a pyridine-N-oxide moiety is reacted with an inert solvent such as methanol, ethanol, etc. Palladium catalyst, preferably palladium on activated carbon, in toluene or 2-propanol Reduction to the corresponding pyridine I-3 under transfer hydrogenation conditions using metal metal. Shiku Rohexene, 1,4-cyclohexadiene, formic acid and formate, such as potassium formate Or aluminum formate is usually used as the hydrogen transfer reagent in this type of reaction. Used. The methyl ester of 1-3 is converted to an aqueous base such as Li in aqueous THF. Hydrolysis with OH or NaOH in aqueous methanol or ethanol The intermediate carboxylate is acidified with a suitable acid, such as TFA or HCl, and This gives the boronic acid I-4. Alternatively, the intermediate carboxylate can be isolated. The carboxylic acid of the free carboxylic acid, if desired or by methods known to those skilled in the art. Salts can also be prepared.   Compounds of formula (I) can also be prepared by alternative methods well known to those skilled in the art. For example, the ether linkage of the compound of formula (I) is R including a group capable of substituting a chloro group, for example, a chloro, bromo or iodo group^Two-Compound It may be formed by reacting with a substance. Utilize other ether-forming reactions And such reactions will be apparent to those skilled in the art.Scheme II a) 2- [N- (3-hydroxy-1-propyl) -N- (tert-butoxycarbonyl) amido No] pyridine-N-oxide, DEAD, (Ph)_ThreeP, DMF; b) LiHMDS, odor 4-trifluoromethylbenzyl compound, DMF; c) cyclohexene, 10% Pd / C, 2-propanol; d) 1.0 N NaOH, MeOH; e) HCl / diox Sun;   Compound II-1 prepared as described in Scheme I was detailed in Scheme I Mitsunobu-type coupling reaction allows 2- [N- (3-hydroxy-1-propyl) -N- (te rt-butoxycarbonyl) amino] pyridine-N-oxide. Got The product, II-2, is placed in position 2 (benzazene) under standard alkylation conditions well known to those skilled in the art. Pin numbering) can be alkylated. For example, II-2 In a medium, usually THF, DMF, DME or a mixture thereof, a base such as hydrogenation Amide by reaction with sodium, LDA or lithium hexamethyldisilazide N-H can be deprotonated. The resulting anionic compound is Reacting with an electrophile, such as an alkyl or benzyl halide, A killing is performed to obtain a product, for example, II-3. Skiing N-3 oxide of II-3 Reduction as described in Scheme I affords II-4, which is described in Scheme I. Can be saponified to II-5. Deprotection of II-5 to obtain II-6 is based on Gr eene, “Protective Groups in 0rganic Synthesis” (published by Wiley-Interscience) ) Can be carried out under standard acidic conditions as described in Such conditions are known to those skilled in the art. It is well known. Also, the conversion of II-3 to II-6 may be performed in another order, for example, II- 3 by Boc deprotection followed by reduction of the N-oxide and finally saponification You can do it too.Scheme III a) 2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide, DEAD , (Ph)_ThreeP, DMF; b) LiHMDS, CH_ThreeI, DMF; c) cyclohexene 10% Pd / C, 2-propanol; d) 1.0 N NaOH, MeOH, then Acidification treatment   Compound III-2, prepared as described in Scheme I, is a standard compound well known to those skilled in the art. Under alkylation conditions, bond at position 2 (benzazepine numbering) and pyridine ring Alkylation at both of the nitrogens. For example, III-2 In at least two solvents in a suitable solvent, usually THF, DMF, DME or a mixture thereof. Equivalent of a base, such as sodium hydride, LDA or lithium hexamethyl It can be deprotonated by reacting with disilazide. The resulting anionic The compound is added to an excess of a suitable electrophile, such as an alkyl halide or benzene. To give the product, for example III-3. III-3 Conversion to III-5 follows the methods described in Schemes I and II.Scheme IV a) cyclohexene, 10% Pd / C, 2-propanol; b) HCl / dioxa C) tert-butylacetyl chloride, Et_ThreeN, CH_TwoCl_TwoD) 1.0 N NaO H, MeOH, then acidification   Compound IV-2, prepared from IV-1 by the procedure described in Schemes I-III, is commercially available from Acylation at the nitrogen atom attached to the pyridine ring under standard acylation conditions well known to Can be For example, IV-2 can be replaced with a suitable scavenger, usually triethyl. Ami CH, in the presence of pyridine, diisopropylethylamine or pyridine_TwoCl_TwoIs In a suitable solvent, an acylating agent such as tert-butylacetyl chloride is reacted with IV-3 is obtained. Numerous other methods of acylating amines are known, Standard reference books, eg, “Compendium of Organic Synthetic Methods”, Vol. I-VI (published by Wiley-Interscience). Described in Schemes I-III IV-3 is obtained by saponifying IV-3 as described.                                Scheme V a) 3- (4-nitrobenzyloxycarbonyl) -1-propanol, DEAD, (P h)_ThreeP, DMF, CH_TwoCl_TwoB) H_Two, Pd / C, EtOH; c) 2-methylthio- 2-imidazoline hydroiodide, (i-Pr)_TwoNEt, dimethylacetamide , 10 0 ° C .; d) 1.0 N Li0H, THF, H_TwoO, then acidification   Compound V-1 prepared as described in Scheme I was synthesized as described in Scheme I. 3- (tert-butoxycarbonylamino)- 1-propanol, 3- (benzyloxycarbonylamino) -1-propanol or Is reacted with 3- (4-nitrobenzyloxycarbonylamino) -1-propanol You. Deprotection of the resulting compound V-2 gives V-3. As is well known to those skilled in the art, Deprotection conditions are selected according to the functionality and the protecting group at V-2. For example, V- The p-nitro-Cbz group in 2 is a palladium catalyst, generally palladium on activated carbon or Is Pd (OH) on activated carbon_TwoIn the presence of a suitable solvent, usually methanol, ethanol , In ethyl acetate or a mixture thereof by hydrogenolysis. If desired Hydrocracking can be carried out in the presence of an acid, for example HCl, and the corresponding V-2 Obtain the ammonium salt. V-3 is converted to a base such as diisopropylethylamine In the presence of a suitable solvent such as MeOH, EtOH, DMF or dimethyl alcohol. Reaction with 2-methylthio-2-imidazoline hydroiodide in cetamide V-4 is obtained. Similar conditions for performing related conversions are described in WO95 / 32710. It is listed. Saponification is performed as described in Scheme I to give V-5 .Scheme VI a) 3- (tert-butoxycarbonylamino) -1-propanol, DEAD, (Ph)_ThreeP , DMF, THF; b) TFA, CH_TwoCl_TwoC) 2-bromopyrimidine, Na HCO_Three, EtOH, reflux; d) H_Two, Pd / C, HCl, MeOH; e) K_TwoCO_Three , H_TwoO   Compound VI-3, prepared from VI-1 by the procedure described in Scheme V, was converted to the appropriate acid Scavenger, usually sodium bicarbonate, triethylamine, diisopropyl In the presence of ruethylamine or pyridine, a suitable solvent such as ethanol, D 2-halopyrimidine, generally 2-chloropyrimidine, in MF or dimethylacetamide Reaction with midine or 2-bromopyrimidine gives VI-4. Pirimi of VI-4 Following gin ring Conditions that are reported to effect the transformation of (see, for example, WO 95/32710) To reduce to the corresponding 1,4,5,6-tetrahydropyrimidine ring. This As described above, VI-4 is reacted with a palladium catalyst, preferably in the presence of palladium on activated carbon. Hydrogenolysis in a suitable solvent such as methanol or ethanol. The reaction is It is usually carried out under acidic conditions; it is generally preferred to add an inorganic acid such as HCl. Good. The filtered reaction mixture is_TwoCO_ThreeAnd H_TwoBasification with O to give VI-5 You.                                Scheme VII a) NaH, 4- (trifluoromethyl) benzyl bromide, DMF; b) H_Two, Pd ( OH)_Two/ C, MeOH   Bondinell et al., PCT application WO 93/0095 (published January 7, 1993). And Bondinell et al., By the general procedure described in PCT application WO 94/14776. Compound VII-1 prepared above is reacted with a suitable base, usually sodium hydride or lithium. Aprotic solvent, preferably in the presence of umbis (trimethylsilyl) amide, 4- (trifluoromethyl) benzyl bromide in DMF, THF or a mixture thereof Reaction gives the bisalkylated product VII-2. 4- (trifluoromethyl) of VII-2 (Tyl) benzyl ether can usually be removed by hydrogenolysis, and phenol VII- 3 is obtained. Methods for the hydrogenolysis of benzyl ethers are well known to those skilled in the art, and For example, Greene, “Protective Groups in Organic Synthesis” (Wiley-Interscie nce publication). Then, according to the method described in the above scheme , VII-3 to prepare the compound of formula (I).   The amide coupling reagent used herein is used to form a peptide bond. Means a reagent that can be used. A typical coupling method is carbodii Utilizes amides, activated anhydrides and esters and acyl halides. Typical Specifically, EDC, DCC, DPPA, PPA, BOP reagent, H0Bt, N-hydroxide Reagents such as roxysuccinimide and oxalyl chloride.   Coupling methods for forming peptide bonds are generally known in the art. Is knowledge. Bodansky et al., THE PRACTICE 0F PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984, Ali et al., J. Med. Chem. 29, 984 (1986) and J. Med. Chem., 30, 22. 91 (1987) generally describes the technique. Therefore, it is incorporated herein by reference.   Typically, the amine or aniline is converted to a suitable carbodiimide coupling agent For example, using N, N′-dicyclohexylcarbodiimide (DCC), From 1-hydroxybenzotriazole (HOBt) and dimethylaminopi In the presence of a catalyst such as lysine (DMAP), an appropriate cal Coupling to the boronic acid substrate. The free carboxyl of the appropriately protected acid substrate To form an activated ester, anhydride or acid halide, and then optionally Other methods, such as reacting a suitably protected amine with a free amine in the presence of a base Is also suitable. For example, a protected Boc-amino acid or Cbz-amidino benzoate The carboxylic acid is converted to an anhydrous solvent such as methylene chloride or tetrahydrofuran (THF) Of a base such as N-methylmorpholine, DMAP or a trialkylamine Treated with isobutyl chloroformate in the presence to form an "activated anhydride" It is later reacted with another protected amino acid or the free amine of aniline.   Compounds of formula (I) (R^TwoIs benzimidazole), Nestor et al., J. Med.C hem. 1984, 27, 320. Bennes useful as intermediates in the present invention Zimi Representative methods for preparing dazole compounds are also common in the art, For example, it is described in EP-A-0381033.   The acid addition salt of the compound is prepared, in an appropriate solvent, using standard methods and the parent compound and excess Acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, triflu Manufactured from oloacetic acid, maleic acid, succinic acid or methanesulfonic acid. Ah Certain compounds form acceptable internal salts or zwitterions. Cationic salt Is an excess of an alkaline reagent containing the appropriate cation, for example, Treatment with hydroxides, carbonates or alkoxides or with appropriate amines It is prepared from Li⁺, Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺And NH_Four ⁺Mosquitoes like Thione is a specific example of a cation present in a pharmaceutically acceptable salt.   The present invention also provides a medicament comprising a compound of formula (I) and a pharmaceutically acceptable carrier. A composition is provided. Accordingly, the compounds of formula (I) may be used in the manufacture of a medicament. Can be. Parenteral administration of the pharmaceutical composition of the compound of formula (I) prepared as described above Solution or lyophilized powder. Powder should be mixed with a suitable diluent before use. Or by the addition of another pharmaceutically acceptable carrier. Liquid formulation is slow It can be an impacted isotonic aqueous solution. Suitable diluents include, for example, Saline solution, 5% dextrose in standard water or buffered sodium acetate or Monium solution. Such formulations are particularly suitable for parenteral administration, but Or in a metered dose inhaler or nebulizer for inhalation. Wear. Polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, po Polyethylene glycol, mannitol, sodium chloride or sodium citrate It may be desirable to add excipients such as   These compounds can also be encapsulated, tableted, or emulated for oral administration. It can also be prepared in a solution or syrup. A pharmaceutically acceptable solid or Add a liquid carrier to enhance or stabilize the composition or to prepare the composition. It may be easier. Solid carriers are starch, lactose, calcium sulfate dihydrate, white Soil, magnesium or stearic acid, talc, pectin, red oak A, agar or gelatin. Liquid carriers include syrup, peanut oil, and oli Oil and seira And water. The carrier may also be glyceryl monostearate or dis- Contains sustained release substances, such as glyceryl theate, alone or with wax You may. The amount of solid carrier varies but, preferably, will be about 20 mg per dosage unit. To about 1 g. The pharmaceutical preparation, if necessary, for tablet form, may be milled, mixed, Granulation and compression or, in the case of hard gelatin capsules, grinding, mixing and It is manufactured according to the usual pharmaceutical techniques, including filling and filling. Use liquid carrier Preparations may be syrups, elixirs, emulsions or aqueous or non-aqueous It is in the form of a suspension. Such a liquid formulation may be administered orally directly, or It may be filled in a soft gelatin capsule.   For rectal administration, the compounds of the invention may also include cocoa butter, glycerin, gelatin. Alternatively, excipients such as polyethylene glycol can be combined and molded into suppositories. Wear.   The compounds described herein are antagonists of the vitronectin receptor, and Pathology occurs in ligands or cells that interact with the vitronectin receptor. It is useful for treating diseases caused by the disease. For example, these compounds can reduce bone matrix loss. Useful in the treatment of diseases in which loss forms a medical condition. Thus, this compound is Porosis, hyperparathyroidism, Paget's disease, malignant hypercalcemia, For the treatment of bone metastases due to sex hormone deficiency and osteolytic lesions induced by bone loss Useful. The compounds of the present invention also have antitumor, antiangiogenic, antiinflammatory and antimetastatic Useful in the treatment of atherosclerosis and restenosis It is considered to be.   The compound is sufficient to inhibit the concentration of the drug from inhibiting bone resorption or other such indications. Thus, it is administered to a patient either orally or parenterally. Doctor containing the compound The pharmaceutical composition is used in an amount of about 0.1 to about 50 mg / kg for oral administration according to the patient's condition. Administered in amounts. Preferably, the oral dose is from about 0.5 to about 20 mg / kg. You. For emergency treatment, parenteral administration is preferred. Peptide water or saline Intravenous infusion in 5% dextrose in medium or similar formulation with appropriate excipients While most effective, intramuscular bolus injections are also useful. Typically parenteral dose Is about 0.01 to about 100 mg / kg; preferably 0.1 to 20 mg / kg It is. Compound At a level that provides a total daily dose of from about 0.4 to about 400 mg / kg / day. 1 to 4 times. The precise level and method of administering a compound will depend on the particular By comparing blood levels to those required to achieve a therapeutic effect, It is easily determined by the method used.   The invention further provides compounds of formula (I) and other inhibitors of bone resorption, such as bisphos Sulfonates (ie, alendronate), hormone replacement Phased or physical combination with therapeutics, antiestrogen or calcitonin Administering osteoporosis or inhibiting bone loss. Addition Thus, the present invention provides compounds of the present invention and the prevention of bone loss and / or reduction of bone mass. Bone morphogenetic proteins such as iproflavono Therapeutic methods using a chelating agent are provided.   In addition, the present invention provides compounds of formula (I) and antitumor agents in a stepwise or physical And a method for inhibiting tumor growth. Topote Camptothecin ana such as can, irinotecan and 9-aminocamptothecin Log species and plastics such as cisplatin, ormaplatin and tetraplatin Tina coordination complex compounds are well known as antitumor agents. Camptothe Compounds of the syn analog class are disclosed in US Pat. Nos. 5,0047,458 and 4,604,463. No. 4,473,692, No. 4,545,880, No. 4,342,776, No. 4513 138, 4399276, European Patent Application No. 0418099 and 0088642, Wani et al., J. Med. Chem., 1986, 29, 2358; Wani et al., J. Med. m., 1980, 23, 554, Wani et al., J. Med. Chem., 1987, 30, 1774, and Nitta et al., P. roc.14 th International Congr. Chemotherapy., 1985, Anticancer Section 1 , 28, the entire disclosure of which is hereby incorporated by reference. Step The platinum coordination complex, cisplatin, is available from Platinol® By Name Bristol Myers-Squibb Corporation Squibb Corporation). Useful prescriptions for cisplatin Nos. 5,562,925 and 4,310,515. Is hereby incorporated by reference in its entirety.   Administration of the compound of formula (I) and the antitumor agent stepwise or in physical combination A platinum coordinating compound, such as Splatin can be administered using a slow release intravenous infusion. Preferred The carrier is a dextrose / saline solution containing mannitol. platinum The coordination compound dosing schedule is approximately 1 / m2 of surface area per treatment step. To about 500 mg (mg / m^Two). Platinum coordination The injection of the compound is administered once or twice a week, and the treatment can be repeated several times a week . When administering a compound of the camptothecin analog species parenterally, generally, About 0.1 to about 300.0 mg / m of surface area per day^TwoFor about 5 consecutive days And use a therapeutic step. Most preferably, in therapeutic processes utilizing topotecan Means surface area 1m / day for about 5 consecutive days^TwoAbout 1.0 to about 2.0 mg per day Is administered. Preferably, the treatment process is performed at least about 7 days to about 28 days apart. Repeat once.   A pharmaceutical composition is prepared by combining a compound of formula (I) and an anti-tumor agent together in the same container. However, formulation in a different container is preferred. Drugs are both supplied in solution form If administered, the drug may be in an infusion / injection system for co-administration or tandem allene. Can be included.   It is convenient to administer the compound of formula (I) and the antitumor agent simultaneously or separately. Or individual bottles, in a single container such as a box, carton or other container Including bags, vials or other containers, each of which has a parenteral administration as described above. Having an effective amount of a compound of formula (I) and an effective amount of an antitumor agent for parenteral administration as described above. To produce a kit. Such kits can be, for example, in separate containers or in the same Reconstitute solution with both drugs, optionally as lyophilized plugs Container. This variation uses a reconstitution solution and a lyophilized plug. Can be placed in two chambers in a single container and mixed before use It is. In such an arrangement, an anti-tumor agent and a compound of the invention are It may be packaged separately as in a container, or lyophilized together with powder Finally, it can be supplied in a single container.   When both drugs are supplied in solution form, they are injected / injected for simultaneous administration system Or it can be included in a tandem arrangement. For example, the compound of formula (I) Object was placed in another infusion bag continuously via intravenous injectable form or tube It can also be placed in an infusion bag linked to an antitumor agent. Using such a system In the first case, the patient receives an injection or infusion of a compound of formula (I) in bolus form. The patient may then receive an injection of the antitumor agent.   The compounds are tested in one of several biological assays, and The concentration of the compound required to achieve the effect may be determined.Inhibition of vitronectin binding   α_vβ_ThreeTo solid phase [^ThreeH-SK & F-107260 binding: Buffer T (2 mM chloride) Human placenta or human platelets α in lucium and 1% octylglucoside)_v β_Three(0.1-0.3 mg / ml) in 1 mM calcium chloride, 1 mM manganese chloride 1 mM magnesium chloride (buffer A) and 0.05% NaN_ThreeContained buffer T and then immediately spill into a 96-well ELISA plate (Corning, New York) , NY) in an amount of 0.1 ml per well. 0.1-0.2 per well μg α_vβ_ThreeWas added. Plates were incubated overnight at 4 ° C. At the time of the experiment The wells were washed once with buffer A and treated with 3.5% bovine serum in the same buffer for 1 hour at room temperature. Incubated with 0.1 ml of albumin. After incubation, Was completely aspirated and washed twice with 0.2 ml of buffer A.   Compounds were dissolved in 100% DMSO to obtain a 2 mM stock solution, which was buffered for binding. Buffer solution (15 mM Tris-HCl (pH 7.4), 100 mM sodium chloride, 1 mM calcium chloride, 1 mM manganese chloride, 1 mM magnesium chloride) , 100 pM final compound concentration. This solution is then brought to the desired final compound concentration. Diluted. Various concentrations of unlabeled antagonist (0.001-100 pM) Added to wells in triplicate then 5.0 nM [^ThreeH] -SK & F-10726 0 (65-86 Ci / mmol) was added.   Plates were incubated for 1 hour at room temperature. After incubation, Aspirate completely and in a well-to-well manner, add 1 ml with 0.2 ml ice-cold buffer A. Washing Was cleaned. The receptor was solubilized with 0.1 ml of 1% SDS and Beckman LS liquid synth Add 3 ml of Ready Safe at the chelation counter And binding by liquid scintillation counting with 40% efficiency [^ThreeH] -SK & F -107260 was measured. In the presence of 2 μM SK & F-107260, [^ThreeH] -Measure non-specific binding of SK & F-107260 and consistently measure total radioligand It was 1% or less of the input amount. Non-linearity modified from LUNDON-2 program The least squares curve fitting routine allows the IC₅₀([^ThreeH] -SK & F-107260 Antagonist concentration that inhibits binding by 50%) was determined. Equation: Ki = IC₅₀/ (1 + L / K_d) (Where L and K_dAre each [^ThreeH] -SK & F-107260 Ki (dissociation constant of antagonist) according to concentration and dissociation constant did.   The compounds of the present invention are available in a concentration range from about 4.0 to about 0.0003 μM of SK & F- Inhibits vitronectin binding to 107260.   Assess inhibition of bone formation, such as the pit formation assay disclosed in EP 528587 Assays standard in the art to perform in vitro and in vivo. The compounds of the invention are tested for bone resorption. This assay is described in Wronski et al., Cells a. rat Materials, Sup. 1: 69-74 (1991), rat osteoclasts, And can be performed using human osteoclasts instead of the ovariectomized rat model. No.Vascular smooth muscle cell migration assay   Rat or human aortic smooth muscle cells were used. Polycarbonate with 8 μm holes Transwell cell culturing chamber using a nitrate membrane (Costar) The cell migration in the cell was monitored. Vitronectin on the lower surface of the filter Covered. 2.5-5. In DMEM supplemented with 0.2% bovine serum albumin. 0x10⁶The cells are suspended at a concentration of cells / ml and the test compound at various concentrations at 20 ° C. For 20 minutes. The solvent alone was used as a control. Chamber upper part The compartment received 0.2 ml of the cell suspension. The lower compartment is 0. It contained 0.6 ml DMEM supplemented with 2% bovine serum albumin. 95% air / 5% CO_TwoFor 24 hours at 37 ° C. Incubation After removal, the non-migrating cells on the upper surface of the filter were gently scraped off to remove. Next Meta filter The cells were fixed with Knol and stained with 10% Giessa dye. a) on the lower surface of the filter Count the number of migrated cells or b) extract the stained cells with 10% acetic acid Migration was measured by measuring the absorption at 600 nM.A rat model with thyroid parathyroidectomy   Each experimental group was treated with 5-6 adult male Spurague-Dawley rats (weighing 250-400 g). ). Thyroid parathyroidectomy of rats 7 days before use (Taconic Farm). All rats are given thyroxine every 3 days. When obtaining rats Next, the circulation of whole blood immediately after collection into a test tube treated with heparin by tail vein puncture was performed. Measure calcium onion levels. Ionized Ca level (Ciba-Corning model 634 calcium (measured with a pH analyzer) using rats of <1.2 mM / l You. Each rat was used for test substance delivery and for blood sampling. Indwelling venous and arterial catheters are each installed. The rats are then given calcium Give free diet and deionized water. Measure the base level of Ca level, By continuous infusion into the vein through a vascular catheter using a syringe pump, Control vehicle or human parathyroid hormone 1-34 peptide (hPTH1-3 4. The dose is 1.25 μg / kg / hr in saline / 0.1% bovine serum albumin In the meantime, a mixture of Bacham, Ca) or hPTH1-34 and the test substance is administered to each rat. Give. The calcium blood response of each rat was measured at 2 hour intervals during the 6-8 hour infusion. Set.Human osteoclast resorption and adsorption assay   Pit follicle absorption and adsorption assay using normal human osteoclasts from osteoclastoma tissue Was developed and standardized. Laser confocal microscopy measures osteoclast pit volume Assay 1 was developed. Collagen fragments (released during absorption) by competitive ELISA Assay 2 was developed as a high-throughput screen to measureAssay 1 (using a laser confocal microscope) Removing an aliquot of the cell suspension from human osteoclastoma from liquid nitrogen storage; Warm rapidly at 37 ° C. and centrifuge (1000 rpm, 4 ° C. for 5 minutes) for RPMI Wash once with -1640 medium. -Aspirate media and replace with murine anti-HLA-DR antibody, then RPMI-164 0 Dilute 1: 3 with medium. Incubate the suspension on ice for 30 minutes, frequently Mix. Wash cells twice with cold RPMI-1640 followed by centrifugation (1000 rpm, 4 C. for 5 minutes) and then transfer the cells to a 15 ml sterile centrifuge tube. Improved Neubauer (Neubauer) Count mononuclear cells in counting chamber. -Magnetic beads coated with a sufficient amount of goat anti-mouse IgG (Dynal, Great Neck, NY ) Is removed from the storage bottle and placed in 5 ml of fresh medium (this allows Wash away preservatives). Fix the beads on a magnet, remove the medium, and place in fresh medium. Replace. -Mix beads with cells and incubate suspension on ice for 30 minutes. Suspension Mix frequently. ・ Bead-coated cells are fixed on a magnet, and the remaining cells (fraction rich in osteoclasts) Is decanted into a 50 ml sterile centrifuge tube. -Add fresh medium to the beads-coated cells and wash out any remaining osteoclasts. this Repeat the washing process 10 times. Discard the beads-coated cells. Label viable cells with fluorescent diacetate and use live counting Count the cells. Using a large diameter disposable plastic Pasteur pipette Add sample to chamber. ・ Pellet the osteoclasts by centrifugation, and adjust to the appropriate number of cells in EMEM medium. Adjust the density (the number of osteoclasts varies between tumors), 10% fetal bovine serum and 1 . Replenish with 7 g / l sodium bicarbonate. Decarate 3 ml aliquots of cell suspension (per reaction compound) into 15 ml centrifuge tubes To state Pellet cells by centrifugation. Add 3 ml of the appropriate reaction compound to each test tube (dilute to 50 μM in EMEM medium). Pardon). These include vehicle controls, positive controls (anti-vitro diluted to 100 μg / ml). Nectin receptor murine monoclonal antibody [87MEM1]) and isotype Control (IgG diluted to 100 μg / ml)_2a) Is also included. Samples at 37 ° C And incubate for 30 minutes. • Seed 0.5 ml aliquots of cells into sterile dentin slices of a 48-well plate seed And incubate at 37 ° C. for 2 hours. Screen each reaction in a quadruple test To ・ Replace the warm PBS (well of 10 ml / 6 well plate) 6 times to slice Wash and then place in fresh medium containing reaction compound or control sample. Incubate the sample at 37 ° C. for 48 hours.Tartrate-resistant acid phosphatase (TRAP) method (selective staining of cells of the osteoclast lineage) Washing the bone slice containing the adsorbed osteoclasts with phosphate buffered saline, 2% Fix with glutaraldehyde (in 0.2 M sodium cacodylate) for 5 minutes. -These are then washed with water and incubated for 4 minutes at 37 ° C in TRAP buffer (0.5 mg / ml AS-BI solution dissolved in N, N-dimethylformamide) 0.25 M citrate buffer containing 10 mM sodium tartrate pH 4.5). ・ After washing with cold water, cold acetate containing 1 mg / ml fast red garnet Dip slices in buffer (0.1 M, pH 6.2) and incubate at 4 ° C for 4 minutes. To Aspirate excess buffer, wash slices with water and air dry. -TRAP positive osteoclasts (bright field microscopy) (Red brick / purple precipitate) and then removed from the dentin surface by sonication . ・ By Nikon / Lasertec ILM21W confocal microscope Measure pit volume.Assay 2 (using ELISA readout)   Enrich for human osteoclasts as described in the first 9 steps of assay 1, Prepare for screening. For clarity, these steps are repeated below . Removing an aliquot of the cell suspension from human osteoclastoma from liquid nitrogen storage; Warm rapidly at 37 ° C. and centrifuge (1000 rpm, 4 ° C. for 5 minutes) for RPMI Wash once with -1640 medium. -Aspirate media and replace with murine anti-HLA-DR antibody, then RPMI-164 Dilute 1: 3 with 0 medium. Incubate the suspension on ice for 30 minutes, Mixed Combine. Wash cells twice with cold RPMI-1640 followed by centrifugation (1000 rpm, 4 C. for 5 minutes) and then transfer the cells to a 15 ml sterile centrifuge tube. Improved Neubauer (Neubauer) Count mononuclear cells in counting chamber. -Magnetic beads coated with a sufficient amount of goat anti-mouse IgG (Dynal, Great Neck, NY ) Is removed from the storage bottle and placed in 5 ml of fresh medium (this allows Wash away preservatives). Fix the beads on a magnet, remove the medium, and place in fresh medium. Replace. -Mix beads with cells and incubate suspension on ice for 30 minutes. Suspension Mix frequently. ・ Bead-coated cells are fixed on a magnet, and the remaining cells (fraction rich in osteoclasts) Is decanted into a 50 ml sterile centrifuge tube. -Add fresh medium to the beads-coated cells and wash out any remaining osteoclasts. this Repeat the washing process 10 times. Discard the beads-coated cells. Label viable cells with fluorescent diacetate and use live counting Count the cells. Using a large diameter disposable plastic Pasteur pipette Add sample to chamber. ・ Pellet the osteoclasts by centrifugation, and adjust to the appropriate number of cells in EMEM medium. Adjust the density (the number of osteoclasts varies between tumors), 10% fetal bovine serum and 1 . Replenish with 7 g / l sodium bicarbonate. • In contrast to the method described above for Assay 1, IC as outlined below₅₀ Screen compounds at 4 doses to obtain: Pre-prepare osteoclast preparation with test compound (4 doses) or control for 30 minutes at 37 ° C And incubate. These are then added to bovine cortical slices in the wells of a 48-well tissue culture plate Seed and incubate further at 37 ° C. for 2 hours. Wash bone slices with 6 changes of warm phosphate buffered saline (PBS) Remove adsorbed cells, then 48-well plate containing new compound or control Return to the well. -The tissue culture plate is then incubated for 48 hours at 37 ° C. Aspirate the supernatant of each well into individual tubes and release type I collagen during the absorption process Screening by competitive ELISA to detect c-telopeptide. this is 8 amino acids present in the carboxy-terminal telopeptide of the a1 chain of type I collagen Acid sequence (Glu-Lys-Ala-His-Asp-Gly-Gly-Arg) ELISA containing a rabbit antibody that specifically reacts with Osteometer, Denmark). Results are expressed as% inhibition of absorption compared to vehicle control .Human osteoclast adsorption assay   Enrich for human osteoclasts as described in the first 9 steps of assay 1, Prepare for screening. For clarity, these steps are repeated below . Removing an aliquot of the cell suspension from human osteoclastoma from liquid nitrogen storage; Warm rapidly at 37 ° C. and centrifuge (1000 rpm, 4 ° C. for 5 minutes) for RPMI Wash once with -1640 medium. -Aspirate media and replace with murine anti-HLA-DR antibody, then RPMI-164 Dilute 1: 3 with 0 medium. Incubate the suspension on ice for 30 minutes, Mix. Wash cells twice with cold RPMI-1640 followed by centrifugation (1000 rpm, 4 C. for 5 minutes) and then transfer the cells to a 15 ml sterile centrifuge tube. Improved Neubauer (Neubauer) Count mononuclear cells in counting chamber. -Magnetic beads coated with a sufficient amount of goat anti-mouse IgG (Dynal, GreatNeck, NY ) Is removed from the storage bottle and placed in 5 ml of fresh medium (this allows Wash away preservatives). Fix the beads on a magnet, remove the medium, and place in fresh medium. Replace. -Mix beads with cells and incubate suspension on ice for 30 minutes. Suspension Mix frequently. ・ Bead-coated cells are fixed on a magnet, and the remaining cells (fraction rich in osteoclasts) Is decanted into a 50 ml sterile centrifuge tube. -Add fresh medium to the beads-coated cells and wash out any remaining osteoclasts. this Repeat the washing process 10 times. Discard the beads-coated cells. Label viable cells with fluorescent diacetate and use live counting Count the cells. Using a large diameter disposable plastic Pasteur pipette Add sample to chamber. ・ Pellet the osteoclasts by centrifugation, and adjust to the appropriate number of cells in EMEM medium. Adjust the density (the number of osteoclasts varies between tumors), 10% fetal bovine serum and 1 . Replenish with 7 g / l sodium bicarbonate. Osteoclasts from osteoclastoma at 37 ° C with compound (4 doses) or control Incubate for 30 minutes. • Then slide the cells coated with osteopontin (human or rat osteopontin). Opontin, 2.5 μg / ml) and incubate at 37 ° C. for 2 hours . Wash the slides vigorously with phosphate-buffered saline to remove non-adsorbed cells, The cells remaining in the ride are fixed with acetone. Sake, a selective marker for cells of this phenotype (see steps 15-17) Stain osteoclasts for tartrate-resistant acid phosphatase (TRAP), light microscopy Count by the method. Results are expressed as% adsorption inhibition compared to vehicle control.Cell adsorption assay Cells and cell culture   Human embryonic kidney cells (HEK293 cells) were obtained from ATCC (catalog number: CRL 1573). Earl's salt, 10% fetal bovine serum, 1% Earl's Minimum Essential Medium (E) containing glutamine and 1% penicillin-streptomycin Cells were grown in arl's minimal essential medium (EMEM).Construction and transfection   Blunt end ligation allows for CMV promoter and selectable G EcoRI- of pCDN vector containing 418 marker (Aiyar et al., 1994) At the EcoRV cloning site, α_v3.2 kilobase EcoR of subunit I-KpnI fragment and β_Three2.4 kilobase XbaI of subunit -The Xhol fragment was inserted. For stable expression, Gene Pal Α using Gene Pulser (Hensley et al., 1994)._v+ Β construct (each subunit Set DN A 20 μg) and 80 × 10⁶HEK293 cells were electrotransformed and 100 mm Plate (5x10^Five(Cell / plate). After 48 hours, add 45 0 μg / ml gentisin (G418 sulfate, GIBCO-BRL, Beathesda, MD). Select cells in selection media until colonies are large enough for the assay. The vesicles were retained.Immunocytochemical analysis of transfected cells   HEK293 transfectants express vitronectin receptor Fix cells on a microscope glass slide by centrifugation to determine if Fix with acetone for 2 minutes at room temperature and air dry. Using standard indirect immunofluorescence And α_vβ_ThreeSpecific reaction with 23C6, a monoclonal antibody specific for the complex Showed sex.Cell adsorption experiment   0.1 ml of human vitronectin (0.2 μg / ml in RPMI medium) Corning 96-well ELISA plates were pre-coated overnight at 4 ° C. . At the time of the experiment, the plates were washed once with RPMI medium and 3.5% BS in RPMI medium. A for 1 hour at room temperature. 20 mM Hepes, pH 7.4 and 0.1% BSA 293 cells transfected in RPMI medium supplemented with⁶ Resuspended at a density of cells / ml. Add 0.1 ml of cell suspension to each well, Various α_vβ_ThreeIncubate at 37 ° C for 1 hour in the presence or absence of antagonist I did it. After incubation, a 10% formaldehyde solution, pH 7.4, 0.025 ml was added and the cells were fixed at room temperature for 10 minutes. 0.2 ml of RPMI Wash plate three times with medium and add 0.1 ml 0.5% toluidine blue at room temperature The adsorbed cells were stained for 20 minutes. Multiple washes with deionized water to remove excess dye Was. By adding 0.1 ml of 50% ethanol containing 50 mM HCl, Toluidine blue incorporated into the cells was eluted. Microtiter plate Use a reader (Titertek MultiskanMC, Sterling, VA) at an optical density of 600 nm. Cell adsorption was quantified.Solid-phase α _v β ₃ binding assay   Vitronectin receptor α from human placenta_vβ_ThreeWas purified. 50 mM Tris- HCIN, pH 7.5, 100 mM NaCl, 1 mM CaCl_Two, 1 mM Mn Cl_Two, 1 mM MgCl_TwoDilute the receptor preparation with (Buffer A) and immediately add 9 0.1 ml was added per well to a 6-well ELISA plate. α_vβ_ThreeThe 0.1-0.2 μg was added per well. Incubate the plate at 4 ° C overnight Was. The wells were washed once with buffer A during the experiment, and 3.5% bovine serum was added in the same buffer. Incubate with 0.1 ml of albumin for 1 hour at room temperature. Incubation After washing, the wells were completely aspirated and washed twice with 0.2 ml of buffer A.   [^ThreeH] -SK & F-107260 competition assay at various concentrations of unlabeled Antagonist (0.001-100 μM) is added to the wells and then 5.0 nM [^ThreeH] -SK & F-107260. Incubate the plate at room temperature for 1 hour I did it. After the incubation, the wells are completely aspirated and the well-to- The wells were washed once with 0.2 ml of ice-cold buffer A in the same manner as described above. 1% SDS 0.1m 1 to solubilize the receptor, Beckman LS6800 liquid scintillation Add 3 ml of Ready Safe at the application counter and add 4 ml. Binding by liquid scintillation counting method with 0% efficiency [^ThreeH] -SK & F-10 7260 was measured. In the presence of 2 μM SK & F-107260, [^ThreeH] -SK & Non-specific binding of F-107260 was measured and consistently measured for total radioligand input. It was less than 1%. Nonlinear least squares modified from LUNDON-2 program IC by curve fitting routine₅₀([^ThreeH] -SK & F-107260 binding to 50 % Inhibitory concentration). Cheng and Prusoff equations: Ki = IC₅₀/ (1 + L / K_d) (Where L and K_dAre each [^ThreeH-SK & F-1072 Ki (antagonist dissociation constant) according to a concentration of 60 and a dissociation constant). Calculated.Inhibition of RGD-mediated GPIIb-IIIa binding Purification of GPIIb-IIIa   3% octyl glucoside, 20 mM Tris-HCl, pH 7.4, 140 mM NaCl, 2 mM CaCl_TwoStir gently at 4 ° C for 2 hours and wash for days Ten units of human platelets (obtained from the Red Cross) were lysed. 100,000 g of melt Centrifuged for 1 hour. 20 mM Tris-HCl, pH 7.4, 100 mM NaCl , 2m MCaCl_Two5 ml buffer pre-equilibrated with 1% octyl glucoside (buffer A) Apply the supernatant obtained on a lentil lectin Sepharose 4B column (E.Y.Labz) did. After incubation for 2 hours, the column was washed with 50 ml of cold buffer A . Dissolve GPIIb-IIIa holding lectin in buffer A containing 10% dextrose. Issued. All steps were performed at 4 ° C. By SDS polyacrylamide gel electrophoresis It was shown that GPIIb-IIIa having a purity of> 95% was obtained.Uptake of GPIIb-IIIa in liposomes   Phosphatidylserine (70%) and phosphatid The mixture of zircholine (30%) (Avanti Polar Lipids) was dried. Purification G PIIb-IIIa was diluted to a final concentration of 0.5 mg / ml and the protein: It was mixed with phospholipids at a quality ratio of 1: 3 (weight: weight). Resuspend the mixture and mix Sonicated in a nicator bath for 5 minutes. Then 12000-14000 molecular weight Using a dialysis tube to separate, a 1000-fold excess of 50 mM Tris-HCl, pH7. 4, 100 mM NaCl, 2 mM CaCl_Two(Change twice) mixed overnight The mixture was dialyzed. GPIIb-IIIa-containing liposome at 12000 g for 15 minutes And resuspended in dialysis buffer at a final protein concentration of about lmg / ml. Liposomes were stored at -70 ° C until needed.Competitive binding to GPIIb-IIIa   As an RGD-type ligand [^ThreeIndirect competition using [H] -SK & F-107260 Binding to fibrinogen receptor (GPIIb-IIIa) by binding method Tested. 96 wells using 0.22 μm hydrophilic durapore membrane Filter plate assembly (Millipore Corporation, Bedford, MA) A combined assay was performed. 10 μg / ml polylysine (Sigma Chemical Co., St. Louis) (s, MO) Pre-coat wells with 0.2 ml for 1 hour at room temperature to block non-specific binding Refused. Various concentrations of unlabeled benzazepine were added to the wells in a quadruplicate test. [^ThreeH ] -SK & F-107260 at a final concentration of 4.5 nM to each well, then One microgram of purified platelet GPIIb-IIIa-containing liposomes was added. Mix room Incubated for 1 hour at warm. Using Millipore filtration manifold By filtering GPIIb-IIIa binding from unconjugated [^ThreeH] -SK & F-107260 And then washed with ice-cold buffer (2 times with 0.2 ml each). 40% efficient bed For Beckman liquid scintillation counter (LS6800 model) 1.5 ml Ready Solve (Beckman Instruments, Fu (llerton, CA) to count the bound radioactivity remaining on the filters. 2 μM unlabeled Nonspecific binding was measured in the presence of SK & F-107260 and consistently added to the sample. It was 0.14% or less of the total radioactivity obtained. All data are averages of quadruplicate tests . Competition binding data was analyzed by non-linear least squares curve fitting. By this method Antagonist IC₅₀(At equilibrium,^ThreeH] -SK & F-107260 specific Antagonist concentration that inhibits binding by up to 50%). IC₅₀Is Cheng And Prusoff equation: Ki = IC₅₀/ (1 + L / K_d) (Where L is the competitive binding assay) I used [^ThreeH] -SK & F-107260 (4.5 nM), and Kd is 4.5 nM [determined by Scatchard analysis^ThreeH] -Is the dissociation constant of SK & F-107260). It is related to the separation constant (Ki).   Preferred compounds of the present invention have a 10: 1 or less relative to fibrinogen receptor. It has strong vitronectin receptor affinity on top. The most preferred compound is 1 It has an activity of 00: 1 or more.   Using several transplanted mouse tumor models, the compound of formula (I) alone or Alternatively, the effect in combination with the antineoplastic agent can be determined. For details on these models See U.S. Patent Nos. 5,500,458 and 5,633,016.   The following examples do not limit the scope of the invention in any way. Provided for the description of the preparation and use of the compound of the present invention. Many other Embodiments will be readily apparent to those skilled in the art.                                  Example                                General matters   ¹1 H nuclear magnetic resonance (NMR) spectra were obtained at either 250 or 400 MHz. Recorded. Chemical shifts in low fields from the internal standard tetramethylsilane Million Reported in minutes (δ). Abbreviations for NMR data are as follows: s = Singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet Doublet, dt = triplet doublet, app = clear, br = broad. J represents an NMR coupling constant measured by Hertz. CDCl_ThreeIs deuterium chroma Roform, DMSO-d₆Is hexadeuterium dimethyl sulfoxide, CD_ThreeOD is tetradeuterium methanol. Infrared (IR) spectrum is transmitted Mode, and the band position is the reciprocal of the wavelength (cm^-1). Mass spectrum Was obtained using electrospray (ES) or FAB ionization techniques. Elemental analysis Quantita, with an address within the organization or in the White House, NJ tive Technologies Inc. Went in either. Melting point is Thomas Hoover melting Measured using point equipment and uncorrected. All temperatures are reported in degrees Celsius. Analte c Place Silica Gel GF and E. Merck Silica Gel 60F-254 Used for toography. Flash and gravity chromatography by E. Merch Ki Performed on eselgel 60 (230-400 mesh) silica gel. Analytical and preparative H PLC was performed on a Rainin or Beckman chromatograph. ODS is octadecyl Refers to a silyl-derived silica gel chromatographic support. 5μ Apex-ODS Nominally manufactured by Jones Chromatography, located in Littleton, Lorad Refers to an octadecylsilyl-derived silica gel chromatographic support with a particle size of 5μ. Y MC ODS-AQ® is an ODS chromatographic support, Is a registered trademark of YMC Co. Ltd., having an address in Kyoto, Japan. PRP-1 (registered trademark) ) Is a polymer (styrene-divinylbenzene) chromatographic support, A registered trademark of Hamilton Co., with address in Reno, Vada. Celite (Register (Trademark) is a filter aid consisting of acid-washed diatomaceous earth silica. A registered trademark of Manville Corp., with address.                                 Preparation Example 1 ( ±) -8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzaze Preparation of pin-4-methyl acetate a) 4-bromo-3-bromomethylanisole   2-bromo-5-methoxytoluene (20 g, 0.10 mol), N-bromosuccine Imide (19.6 g, 0.11 mol), benzoyl peroxide (1 g, 4 mmol) And methylene chloride (200 mL) with a floodlight for 18 hours and gentle reflux Was done. The mixture is then cooled to -10 ° C for several hours and decanted. The solution and the precipitated succinimide were separated. Concentrate the solution and remove the residue in chloroform. Crystallized from hexane / hexane to give the title compound as pale yellow prisms (19.7 g, 70%).b) 3-bis (tert-butoxycarbonyl) aminomethyl-4-bromoanisole   4-bromo-3-bromomethylanisole (24 g, 86 mmol) and di-te Potassium rt-butyliminodicarboxylate (24 g, 94 mmol) The mixture in lumamide (200 mL) was stirred at room temperature under argon for 18 hours. The reaction was then concentrated under vacuum and the residue was partitioned between ethyl acetate and water. Organic The phases were washed with water and brine, dried (magnesium sulfate) and concentrated. Residue Was recrystallized from hexane to give the title compound (15 g, 42%) as a white solid. . c) (±) -3-carbomethoxy-4- [2-bis (tert-butoxycarbonyl) aminome Methyl butyl-4-methoxyphenyl] -3-butenoate   3-bis (tert-butoxycarbonyl) aminomethyl-4-bromoanisole (15 g, 36 mmol), dimethyl itaconate (7.5 g, 47 mmol), tri-o- Tolylphosphine (1 g, 3 mol), palladium acetate (0.4 g, 2 mmol) , Diisopropylethylamine (12.8 mL, 72 mmol) and propio The nitrile (150 mL) was placed in a 500 mL flask. The mixture is purged with argon. (Several vacuum / argon flush cycles) and then under argon The mixture was refluxed for 1 hour. The reaction was cooled to room temperature and then ice-cold ethyl ether ( 500mL) in Poured into. The resulting precipitate was removed by filtration, and the filtrate was concentrated. Silica gel residue Purify by chromatography above (10% -20% ethyl acetate in hexane) The title compound was obtained as a yellow oil (11.8 g, 66%).d) (±) -3-carbomethoxy-4- [2-bis (tert-butoxycarbonyl) aminome Methyl [4-methylphenyl] butanoate   (±) -3-Carbomethoxy-4- [2-bis (tert-butoxycarbonyl) aminomethyl Methyl 4-butenylate] (11.8 g), ethyl acetate (12 0 mL) and 10% palladium on activated carbon (1 g). Shake under si hydrogen for 18 h. The mixture is then filtered and the filtrate is concentrated to The title compound (12 g, 100%) was obtained as a colored oil. e) (±) -3-carbomethoxy-4- [2- (aminomethyl) -4-methoxyphenyl] Methyl butanoate   (±) -3-Carbomethoxy-4- [2-bis (tert-butoxycarbonyl) aminomethyl Methyl 4-methoxyphenyl] butanoate (12 g) in chloroform (100 m L) and a solution in trifluoroacetic acid (50 mL) at room temperature under argon for 4 hours Stirred. The solution was then concentrated in vacuo to give the title compound as a viscous oil (10 g, 10 g). 0%). MS (ES) m / e 296.2 (M + H)⁺. f) (±) -8-Methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzau Zepin-4-methyl acetate   (±) -3-carbomethoxy-4- [2- (aminomethyl) -4-methoxyphenyl] buta Methylate (10 g, 24 mmol) and triethylamine (17 mL, 12 (0 mmol) in toluene (100 mL) was heated at reflux for 18 hours. The reaction was then concentrated and the residue was partitioned between ethyl acetate and water. The aqueous layer is Extract twice with chill, wash the combined organic extracts with brine, dry (magnesium sulfate) ) And concentrated to give the title compound (4.8 g, 76%) as a pale yellow solid. MS (ES) m / e 264.2 (M + H)⁺. g) (±) -8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benz Azepine-4-methyl acetate   Anhydrous aluminum chloride (7.6 g, 57 mmol) was added under argon at 0 ° C. (± ) -8-Methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine- 4-Methyl acetate (3.0 g, 11 mmol) and ethanethiol (4.2 mL) (57 mmol) in a stirred solution in methylene chloride (100 mL). The resulting mixture was warmed to room temperature, stirred overnight and concentrated. Triturate the residue with ice water The resulting solid was collected by filtration and dried to give the title as an off-white solid The compound (2.64 g, 91%) was obtained. MS (ES) m / e 250.2 (M + H )⁺.                                 Preparation Example 2 ( ±) -8-Hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2- Preparation of methyl benzazepine-4-acetate a) 3- [N- (tert-butoxycarbonyl) -N-methylamino] methyl-4-bromoa Nisole   40% aqueous methylamine (49 mL, 563 mmol) was added at room temperature to 4-bromo- 3-Bromomethylanisole (15.76 g, 56.29 mmol) in THF (2 (80 mL). After 2.5 hours, the reaction was concentrated and the residue was Between ethyl ether (560 mL) and 1.0 N sodium hydroxide (100 mL) Distributed. Separate the layers, dry the organic layer (magnesium sulfate) and concentrate to a yellow oil. Shrunk. TLC (5% methanol / chloroform) R_f0.32.   The oil was dissolved in chloroform (280 mL) and di-tert-butyl dicarbonate (1. 29 g, 56.29 mmol) were added. The reaction was stirred at room temperature for 45 minutes, And concentrated. For silica gel chromatography (5% ethyl acetate / toluene) This gave the title compound (16.81 g, 90%) as a light yellow oil. TLC (5 % Ethyl acetate / toluene) R_f 0.43;¹HNMR (400, CDCl_Three) Rotamer (rotamer) mixture; MS (ES) m / e 352/354 (M + Na)⁺. b) (±) -3-carbomethoxy-4- [2- [N- (tert-butoxycarbonyl) -N-methyl Amino] methyl] -4-methoxyphenyl] butanoic acid methyl   3- [N- (tert-butoxycarbonyl) -N-methylamino] methyl-4-bromoani Sole (4.95 g, 15 mmol), dimethyl itaconate (3.08 g, 19. 5 mmol), palladium acetate (168 mg, 0.75 mmol), tri-o-to Rylphosphine (457 mg, 1.5 mol) and diisopropylethylamine (5.2 mL, 30 mmol) in propionitrile (150 mL) Heated to reflux for minutes and then concentrated on a rotavap. Residue Was diluted with ethyl ether (150 mL), and the mixture was passed through Celite®. And filtered to remove insolubles. The filtrate is concentrated and the residue is concentrated again from xylene. Was. Chromatography on silica gel (gradient: 20% ethyl acetate / hexane, Then phosphine and baseline Remove the quality, R_f 0.40-0.70 All other substances are collected together and concentrated A cloudy yellow oil was obtained: TLC (30% ethyl acetate / hexane) R_f 0.41 ( Main product).   Dissolve the oil in methanol (75 mL) and carefully add 10% Pd / C Was. The mixture was shaken under hydrogen (50 psi) for 2.5 hours and then passed through celite. And filtered to remove the catalyst. The filtrate was concentrated and the residue was again subjected to reaction conditions. Further 2.5 After time, the mixture was filtered through celite to remove the catalyst and the filtrate was concentrated to a light yellow A colored oil was obtained. This is again concentrated from chloroform / hexane, and the silica gel Chromatography (gradient: 20% ethyl acetate / hexane, then 1: 1 ethyl acetate / Hexane) to give the title compound (4.53 g, 74%) as a light yellow oil. Obtained: TLC (30% ethyl acetate / toluene) R_f 0.46;¹HNMR (400 , CDCl_Three) Mixtures of rotamers; c) (±) -3-carbomethoxy-4- [2- (methylamino) methyl-4-methoxyphenyl [R] methyl butanoate   TFA (55 mL) was added to (±) -3-carbomethoxy-4- [2- [N- (tert-butoxy). Carbonyl) -N-methylamino] methyl-4-methoxyphenyl] butanoate ( 4.53 g (11.06 mmol) in anhydrous dichloromethane (55 mL) at 0 ° C. The solution was added all at once and the reaction was warmed to room temperature. After 1 hour, concentrate the reaction And reconcentrate the residue again from toluene (2 × 100 mL) and label as a light yellow oil Compound (11.06 mmol, quantitative) was obtained: MS (ES) m / e 310 (M + H).⁺ . d) (±) -8-methoxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H- 2-benzazepine-4-methyl acetate   (±) -3-carbomethoxy-4- [2- (methylamino) methyl-4-methoxyphenyl ] Methyl butanoate (11.06 mmol) and diisopropylethylamine (5 .8 mL, 33.18 mmol) in toluene (110 mL) at reflux temperature. Heat for 5 hours, stir at room temperature for 4 days, then heat at reflux for another 24 hours . Concentrate and concentrate on silica gel chromatography (ethyl acetate / chloroform (1: 1). 1% methanol in 1) to give the title compound as a light yellow solid: TLC (acetic acid ethyl/ 5% methanol in chloroform (1: 1) R_f 0.63;e) (±) -8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H -2-Benzazepine-4-methyl acetate   Anhydrous aluminum chloride (1.35 g, 10.15 mmol) was added under argon under 0 At (±) -8-methoxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H- Methyl 2-benzazepine-4-acetate (562 mg, 2.03 mmol) and eta Thiol (0.75 mL, 10.15 mmol) in anhydrous dichloromethane (20 m L) was added all at once to the solution. The mixture was warmed to room temperature and stirred for 4.5 hours. The mixture was stirred and then cooled again to 0 ° C. Add ice-cold water (20 mL) and shake the mixture vigorously Stir for 5 minutes and then extract with chloroform (3 × 20 mL). Combined chloro The form layer was dried (magnesium sulfate) and concentrated to give a residue. Suction filtration of aqueous layer To collect the solid precipitate. This precipitate and the residue from the chloroform layer are Combined with hexane / chloroform (1: 1) and concentrated the solution to give an off-white solid. Was. Triturate this material with hot methanol and bring the mixture to room temperature. Cool. Collect solids by suction filtration and wash continuously with cold methanol and water did. Dry at 40 ° C. under high vacuum to give the title compound (467.9) as a colorless solid. mg, 88%): TLC (5% methanol / chloroform) R_f 0.17; Preparation Example 3 Preparation of 2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide a) 2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide   2-Chloropyridine-N-oxide (16.6 g, 0.1 mol), 3-amino-1-prop Lopanol (15.3 mL, 0.2 mol), sodium bicarbonate (42 g, 0.5 Mol) and tert-amyl alcohol (100 mL) were heated to reflux. 21:00 After a while, the reaction is cooled, diluted with dichloromethane (300 mL) and filtered with suction. Insolubles were removed. The filtrate was concentrated and concentrated again from toluene to give a yellow oil. Shi Yellow after Ricagel chromatography (20% methanol / chloroform) The title compound was obtained as a solid (15.62 g, 93%): TLC (20% methanol / Chloroform) R_f 0.48; Preparation Example 4 2-[(3-hydroxy-1-propyl) amino] -4-nitropyridine-N-oxide a) 2-[(3-hydroxy-1-propyl) amino] -4-nitropyridine-N-oxide   2-chloro-4-nitropyridine-in place of 2-chloropyridine-N-oxide hydrochloride N-oxide (Jain, P.C .; Chatterjee, S.K .; Anand, N. Indian Journal of Chemistr y 1966, 403), but according to the procedure of Preparation Example 3 to give the title compound as an orange solid Prepared: MS (ES) m / e 214.2 (M + H)⁺.                                 Preparation Example 5 2-[(3-hydroxy-1-propyl) amino] -4-methoxypyridine-N-oxide a) 2-[(3-hydroxy-1-propyl) amino] -4-methoxypyridine-N-oxy Do   2-[(3-hydroxy-1-propyl) amino] -4-nitropyridine-N-oxide ( 0.275 g, 1 mmol) and 0.5 M sodium methoxide in methanol ( 16 (8 mL, 8 mmol) was heated at reflux under argon for 3 h. Incidentally The reaction was cooled and glacial acetic acid (0.5 mL, 8 mmol) was added. Evaporate the solution to dryness Hardened and the residue was triturated with dichloromethane. Remove insolubles by filtration And the filtrate was concentrated. Silica gel chromatography (5-15% methanol / (Dichloromethane) to give the title compound as a colorless oil (0.23 g, 90%): MS (ES) m / e 199.0 (M + H)⁺.                                 Preparation Example 6 ( ±) -8-hydroxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4, Preparation of 5-tetrahydro-1H-2-benzazepine-4-acetic acid ester a) 3- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) a Mino] methyl-4-bromoanisole   2,2.5,2-trifluoroethylamine (4.9 mL) 62.5 mmol) Anhydrous 4-bromo-3-bromomethylanisole (7.00 g, 25 mmol) in warm water Added quickly to a solution in DMSO (25 mL). Heat the reaction to about 30-35 ° C. Warmed. After 2 hours, the reaction was diluted with ice-cold 0.5N sodium hydroxide (100 mL). And extracted with ethyl ether (3 × 100 mL). Ethyl ether layer combined Was washed successively with water (2 × 25 mL) and brine (25 mL) and dried (sulphuric acid). Magnesium)) and concentrated to a light yellow oil: TLC (toluene) R_f 0.4 3.   Dissolve the oil in anhydrous dichloromethane (48 mL) in a round bottom flask and add dicarbonate -tert-butyl (10.48 g, 48.04 mol) was added. Frus containing reaction solution This was placed on a rotary evaporator and rotated under vacuum at 50 ° C. for 16 hours. . The residue obtained was diluted with hexane (100 mL) and a small amount of pure solid was added to the solution. Isolate product (preliminary experiment using 10% ethyl acetate / hexane as eluent) (Obtained by Ricagel chromatography). Bring the mixture to room temperature for several hours It was left and then placed in the refrigerator overnight. The product is collected by suction filtration and washed with hexane Was cleaned. Dry under vacuum to give the title compound as a colorless solid (7.19 g, 75%). . The mother liquor is concentrated and chromatographed on silica gel (10% ethyl acetate / hexane). Sun) To give the title compound (1.42 g; total 8.61 g, 90%): TLC (10% vinegar) Ethyl acid / toluene) R_f 0.48; melting point 86-89 ° C; b) (±) -3-carbomethoxy-4- [2- [N- (tert-butoxycarbonyl) -N- (2, 2,2-trifluoroethyl) amino] methyl-4-methoxyphenyl] butanoic acid Le   3- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) amido [No] methyl-4-bromoanisole (9.17 g, 23.03 mmol), itacone Dimethyl acid (4.73 g) 29.94 mmol), palladium acetate (259 mg, 1.15 mmol), tri-o-tolylphosphine (701 mg, 2.30 mol) and And diisopropylethylamine (8.0 mL, 46.06 mmol) in propioni Deoxygenate solution in Tril (115 mL) (3x degas / argon purge cycle) And then heated to reflux under argon. After 2 hours, concentrate the reaction And concentrated again from toluene. Silica gel chromatography (30% ethyl acetate Hexane and hexane, dichloromethane). Removing the slime material;_f Combine all other 0.55-0.70 materials and concentrate Shrinkage gave a yellow oil. Dissolve this in 20% ethyl acetate / hexane (200 mL) Then, it was left at room temperature for 1 hour, and then placed in a refrigerator overnight. The mixture was filtered to a yellow precipitate. The residue was removed and the filtrate was concentrated to give a yellow oil (9.93 g, 91%): TLC ( 30% ethyl acetate / hexane) R_f 0.55 (major product).   Dissolve the oil in ethyl acetate (100 mL) and add 10% Pd / C (4.44 g). 18 mmol) was added. The mixture was then placed under hydrogen (50 psi) for 3.5 hours. Shake for one hour and then filter through celite to remove the catalyst. Concentrate the filtrate and leave The residue is chromatographed on silica gel (gradient: 20% ethyl acetate / hexane). To give the title compound as a colorless oil (7.98 g, 73% for 2 steps): T LC (20% ethyl acetate / toluene) R_f 0.35; c) (±) -3-carbomethoxy-4- [2- (2,2,2-trifluoroethylamino) meth Methyl [4-methylphenyl] butanoate   TFA (55 mL) was added at 0 ° C. under argon to (±) -3-carbomethoxy-4- [2- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) amino] Methyl [4-methylphenyl] butanoate (7.98 g, 16.71 mmol) To a solution of anhydrous dichloromethane (42 mL) all at once and allow the reaction to reach room temperature. Was heated. After 1.5 hours, the reaction was concentrated and the residue was concentrated again from xylene did. Dry at 40 ° C. under high vacuum to give the title compound as a yellow solid (8.70 g, quant) Obtained: MS (ES) m / e 378 (M + H).^f. d) (±) -8-methoxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4 , 5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (±) -3-Carbomethoxy-4- [2- (2,2,2-trifluoroethylamino) methyl Methyl 4-methoxyphenyl] butanoate (16.71 mmol), tripropyl Mixing of amine (9.5 mL 50.13 mmol) and xylene (170 mL) The material was heated at reflux. After 63 hours, the reaction was concentrated and the residue was chromatographed on silica. Subjected to chromatography (2: 1 ethyl acetate / hexane, dichloromethane loaded) Was. The title compound (5.33 g, 92% over two steps) was obtained as a light yellow solid. : TLC (40% ethyl acetate / hexane) R_f 0.49; e) (±) -8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H -2-Benzazepine-4-methyl acetate   BBr_ThreeOf dichloromethane in dichloromethane (1.0 M, 60 mL, 60 mmol) was added. Under Lugon at -5 to -10 ° C, (±) -8-methoxy-3-oxo-2- (2,2: 2 -Trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4- Methyl acetate (5.16 g, 14.94 mmol) in anhydrous dichloromethane (60 mL) ) Was added dropwise over 30 minutes. 1 hour at -5 ° C to -10 ° C After this time, the reaction was again cooled completely to −10 ° C. and methanol (60 mL) was added. Quenched carefully with dripping. The reaction was stirred at -10 to 0 ° C for 1 hour. It was then concentrated on a rotary evaporator. Residue is again from methanol (2x) Then, the mixture is concentrated from ethyl acetate and filtered through a silica gel bed (ethyl acetate eluate). I have. Concentrate the filtrate to give a yellow solid, which is triturated with hot hexane did. The title compound (4.74 g, 96%) was obtained as an off-white solid: TLC (1 : 1 ethyl acetate / hexane) R_f 0.40; Preparation Example 7 ( ±) -8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzaze HPLC separation of the enantiomer of pin-4-methyl acetate a) (R)-(+)-8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2- Methyl benzazepine-4-acetate and (S)-(−)-8-hydroxy-3-oxo-2, Methyl 3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   (±) -8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benz A Methyl Zepin-4-acetate was purified by its chiral HPLC under the following conditions. -Diacel Chiralpak AS® column (21.2 x 250 mm ), Ethanol mobile phase, flow rate 7 mL / min, UV detection (254 nm), injection volume 70 mg; (R)-(+)-8-hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2 For benzazepine-4-methyl acetate_RIs 21.5 minutes; (S)-(-)- 8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine- T for 4-methyl acetate_RWas 39.1 minutes.                                 Preparation Example 8 ( ±) -8-Methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepi Separation of enantiomers of methyl 4-methyl acetate a) (R)-(+)-8-Methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-be Nundazepine-4-methyl acetate and (S)-(−)-8-methoxy-3-oxo-2,3,4 , 5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (±) -8-Methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benza Methyl Zepin-4-acetate was purified by its chiral HPLC under the following conditions. -Diacel Chiralpak AS® column (21.2 x 250 mm ), Acetonitrile mobile phase, flow rate 15 mL / min, UV detection (254 nm), injection 500 mg; (R)-(+)-8-methoxy-3-oxo-2,3,4,5-tetrahydro- T for 1H-2-benzazepine-4-methyl acetate_RIs 10.2 minutes and (S) -(-)-8-Methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzaze T for pin-4-methyl acetate_RWas 19.0 minutes.                                 Preparation Example 9 ( S)-(-)-8-Methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benz Demethylation of methyl azepine-4-acetate a) (S)-(−)-8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2- Benzazepine-4-methyl acetate   (S)-(-)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-ben Methyl zeazepine-4-acetate (15.0 g, 0.057 mol) in chloroform (16 0 mL) under argon at −8 ° C., maintaining the temperature at −5 ° C. and 0 ° C. Boron tribromide (20.53 mL, 0.217 mol) over 30 minutes Was added dropwise to a solution in chloroform (160 mL). The reaction mixture is kept at about -8 ° C for 30 Of methanol (200 ml) while maintaining the temperature at about 0 ° C. L) was added dropwise. The reaction mixture was concentrated to give a viscous oil, which was treated with methanol (100 mL). Dissolve the oil in water / methanol and filter to remove a small amount of dark solid. The body was removed. The filtrate was neutralized (pH 7) with 50% sodium hydroxide to give a white solid. Settled. The pH of the suspension was adjusted to 4.5 by adding a small amount of acetic acid and the solid was collected, Dry under vacuum to give the title compound (9.7 g, 68%). The product is HPL C: Chiralpak AS® column (4.6 × 50 mm), 100% ethanol Mobile phase, flow rate 0.5 mL / min, UV detection (215 nm) for chiral purity. Essay; t_R= 7.5 min (S-enantiomer, 99%); t_R= 4.4 minutes (R -Enantiomer, 1%).                                Preparation Example 10 2-[(3-hydroxy-1-propyl) amino] -4,6-dimethylpyridine-N-oxy Preparation of a) 2-[(3-hydroxy-1-propyl) amino] -4,6-dimethylpyridine-NO Oxide   2-chloro-4,6-dimethyl instead of 2-chloropyridine-N-oxide hydrochloride Pyridine-N-oxide (see Brown, E.V., J. Amer. Chem. Soc., 1957, 79, 3565) The title compound was converted to a colorless oil in accordance with the procedure of Preparation Example 4 except that Prepared: MS (ES) m / e 197.2 (M + H)⁺.                                Preparation Example 11 Preparation of 6- (methylamino) -2-pyridylethanol a) 2- (tert-butoxycarbonylamino) -6-picoline   2-amino-6-picoline (4.33 g, 40 mmol), triethylamine (6 0.2 mL, 40 mmol) and dichloromethane (50 mL) at 0 ° C. To the was added di-tert-butyl dicarbonate (9.6 g, 44 mmol). Shake overnight at room temperature After stirring, the reaction mixture was concentrated in vacuo, diluted with water, and dichloromethane (2 × 5). 0 mL). Dry (magnesium sulfate) and concentrate to give the title compound as a colorless oil MS (ES) m / e 209 (M + H)⁺. b) 2-[(tert-butoxycarbonyl) methylamino] -6-picoline   DM of sodium hydride (60% dispersion in mineral oil, 0.44 g, 11 mmol) To a suspension at 0 ° C. in F (20 mL) was added 2- (tert-butoxycarbonylamino) -6-pi A solution of choline (2.1 g, 10 mmol) in DMF (30 mL) was added. reaction The mixture was stirred at 0 ° C. for 15 minutes, then methyl iodide (1.6 g, 11 mmol) was added. added. The reaction mixture is concentrated under vacuum, diluted with water and dichloromethane (3 × 50 mL). Dry (magnesium sulfate) and concentrate to give the title compound as a colorless oil Obtained: MS (ES) m / e 223 (M + H).⁺. c) Ethyl 6-[(tert-butoxycarbonyl) methylamino] -2-pyridylacetate   LDA (18 mmol) was prepared in THF (30 mL), cooled to -78 ° C. 2,2-[(tert-butoxycarbonyl) methylamino] -6-picoline (2 g, 9 mmol ) Was added to form a deep red solution. After 15 minutes, diethyl carbonate (18 mL) , 15 mmol). The magenta solution was stirred at -78 ° C for an additional 15 minutes. The reaction was then quenched with a saturated ammonium chloride solution. Warm the mixture to room temperature And extracted with ethyl acetate (3 × 30 mL). Wash the combined organic layers with brine, Dried (magnesium sulfate) and concentrated. Subjected to silica gel chromatography To give the title compound as a colorless oil: MS (ES) m / e 294 (M + H)⁺. d) Ethyl 6- (methylamino) -2-pyridylacetate   Ethyl 6-[(tert-butoxycarbonyl) methylamino] -2-pyridylacetate (0. 6 g, 2 mmol) and a solution of 4M hydrochloric acid / dioxane (5 mL, 20 mmol) Was stirred overnight at room temperature and then concentrated. Recrystallized from toluene as a white solid To give the title compound: MS (ES) m / e 195 (M + H)⁺. e) 6- (methylamino) -2-pyridylethanol   Mechanical stirring solution of lithium aluminum hydride in THF (1.0 M, 20 mL, 20.4 mmol) in ethyl 6- (methylamino) -2-pyridylacetate (0.38 g). , 2 mmol) in THF (10 mL) was added dropwise. After addition is complete, mix The material was warmed to 0 ° C. and quenched with 10% sodium hydroxide solution. Filter the solids And the filtrate was concentrated under vacuum. Dissolve the residue in dichloromethane and add the solution Was dried (magnesium sulfate) and concentrated. Concentrate again from toluene (3x), The title compound was obtained as a colorless oil: MS (ES) m / e 153 (M + H)⁺.                                Preparation Example 12 Preparation of 3-[(tert-butoxycarbonyl) amino] -1-propanol a) 3-[(tert-butoxycarbonyl) amino] -1-propanol   Di-tert-butyl dicarbonate (10.91 g, 50 mmol) in dichloromethane (5 0 mL) at 0 ° C. with 3-methyl-1-propanol (11.5 mL, 150 mL). mL) in dichloromethane (250 mL). Bring the cloudy solution to room temperature And stirred for 1 hour, then concentrated on a rotary evaporator. Residue Was dissolved in water (100 mL) and extracted with ethyl ether (3 × 100 mL). Dry (magnesium sulfate) and concentrate to give the title compound as a colorless oil: Preparation Example 13 3- ( Preparation of 4-nitrobenzyloxycarbonylamino) -1-propanol a) 3- (4-nitrobenzyloxycarbonylamino) -1-propanol   3-amino-1-propanol (0.77 g, 1.1 mmol) and triethyl Amine (2.85 mL, 7 mmol) in THF (5 mL) under argon at room temperature To the solution stirred at の was added 4-nitrobenzyl chloroformate (2 g, 1 mmol) in TH. Added to the suspension in F (20 mL). The resulting mixture is stirred at room temperature over the weekend. Stir and then concentrate. The residue was chromatographed on silica gel (0% -2% Purification with methanol / dichloromethane gave the title compound as a pale yellow oil (0.80 g, 34%): MS (ES) m / e 254.3 (M + H)⁺.Preparation Example 14 2- [N- (3-hydroxy-1-propyl) -N- (tert-butoxycarbonyl) amino] pi Lysine-N-oxide a) 2- [N- (3-hydroxy-1-propyl) -N- (tert-butoxycarbonyl) amido No] pyridine-N-oxide   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide (8.0 g, 47.6 mmol) in tert-butyl alcohol (80 mL). Reaction with t-butyl (11.4 g, 55.3 mmol). After 18 hours, the solution was Concentrated and the residue was triturated with hexane. Dry the resulting solid under vacuum Drying afforded the title compound (12.5 g, 98%) as an off-white solid: MS (ES ) 269.3 (M + H)⁺.                                Preparation Example 15 ( ±) -8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarbonyl ) Amino] -1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H-2- Preparation of methyl benzazepine-4-acetate a) (±) -8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarbo) Nyl) amino] -1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H- 2-benzazepine-4-methyl acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide -[N- (3-hydroxy-1-propyl) -N- (tert-butoxycarbonyl) amino] pyri The title compound was elucidated according to the procedure of Example 1 (a) except that gin-N-oxide was used. Obtained as an orange foam: MS (ES) m / e 50.4 (M + H)⁺.                                Preparation Example 16 2-[(3-hydroxy-1-propyl) amino] -4-methylpyridine-N-oxide   2-Chloro-4-methylpyridine-N-oxide (12.1 g, 0.068 mol) (Bro wn, E.V., J. Amer. Chem. Soc. 1957, 79, 3565), 3-amino-1-propanol ( 10.33 mL, 0.14 mol), sodium bicarbonate (28 g, 0.34 mol) and And tert-amyl alcohol (70 mL) were heated to reflux. After 16 hours, reactants Is cooled, diluted with dichloromethane (300 mL), and filtered by suction to remove insolubles. did. The filtrate was concentrated and concentrated again from toluene to give a yellow oil. Dichloromethane / Recrystallized from ethyl ether to give the title compound as a yellow solid (10.87 g, 8 8%): TLC (15% methanol / dichloromethane) R_f0.44; Preparation Example 17 ( S) -8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzaze (S) -8-Hydroxy-3-oxo-2- [via alkylation of pin-4-methyl acetate 4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2-ben Preparation of methyl zeazepine-4-acetate a) (S) -3-oxo-8- [4- (trifluoromethyl) benzyloxy] -2- [4- (t Trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2-benzazepi N-4-methyl acetate   (S) -8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-2-H-benza Ze Methyl pin-4-methyl acetate (0.31 g, 1.24 mmol) and 4- (trifluoromethyl) bromide (Romethyl) benzyl (0.89 g, 3.72 mmol) in DMF (10 mL) To the liquor was added sodium hydride (60% suspension in oil, 2.75 mmol). After stirring at room temperature for 4 hours, most of the DMF was removed under vacuum. Saturated carbonic acid residue Partitioned between sodium hydrogen and ethyl acetate. Extract the aqueous phase with ethyl acetate and combine. The organic extracts were washed with saturated sodium chloride, dried over sodium sulfate and concentrated. This gave a colorless oil (0.90 g). Radial chromatography (5% acetone / Dichloromethane, silica gel, 6 meter plate) The compound (0.53 g) was obtained. MS (ES) m / e 566.1 (M + H)⁺. b) (S) -8-Hydroxy-3-oxo-2- [4- (trifluoromethyl) benzyl] -2 , 3,4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (S) -3-Oxo-8- [4- (trifluoromethyl) in a Parr hydrogenation flask Benzyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetra Methyl hydro-1H-2-benzazepine-4-acetate (0.78 g, 1.38 mmol) ) And Pearlman catalyst / methanol (20 mL). 50 After hydrogenation at psi for 24 hours, take out from the reaction vessel and filter to remove the catalyst. Removed. Removal of the solvent gave a white foam (0.60 g). Radical chromatography Lafie (5% acetone / dichloromethane, silica gel, 6 meter plate) To give the title compound as a white foam (0.42 g). Preparation Example 18 (S) -8-Hydroxy-3-oxo-2- [4- (g) via enantioselective synthesis Trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2-benzazepi N- Preparation of 4-methyl acetate a) 4-bromo-3-bromomethylanisole   Dried dichloromethane with 4-bromo-3-methylanisole (100 g, 497 mmol) N-bromosuccinimide (97 g, 5 g) was added to a stirred solution in dichloromethane (500 mL). 45 mmol) followed by benzoyl peroxide (6 g, 25 mmol). Was. The reactants were placed 150 inches with a reflector placed approximately 12 inches away from the reaction flask. Gently refluxed using a watt flood lamp. After 24 hours, the reaction is The volume was reduced to half with a rotary evaporator and allowed to stand for 4 hours. Formation The white precipitate formed was filtered off and rinsed with a small amount of dichloromethane. Concentrate and dry the filtrate And the remaining solid was triturated with hexane and filtered. Dry under vacuum To give the title compound as white needles (100.25 g, 72%): GCt_R= 6. 56 minutes (HP 530 μm × 20 m methyl silicone column, helium carrier -Flow rate 20 mL / min, initial temperature 100 ° C, initial time for 1 minute, 10 ° C / min, final Temperature 200 ° C., 1 minute final time); b) 3- [N- (4-trifluoromethylbenzyl) aminomethyl] -4-bromoaniso Rule   Anhydrous D of 4-bromo-3-bromomethylanisole (35 g, 125 mmol) To a stirred solution in MSO (50 mL) and anhydrous THF (50 mL) was added 4-trifur Oromethylbenzylamine (30 g, 171 mmol) followed by triethyl The amine (18 mL, 129 mmol) was added. After stirring at room temperature for 18 hours, The reaction was concentrated, diluted with aqueous 1N sodium hydroxide (250 mL) and Extracted with water (2 × 250 mL). Wash the combined organic layers with brine and dry (Magnesium sulfate) and concentrated to dryness. The residue formed is filtered on silica gel Purify by flash chromatography (10-20% ethyl acetate / chloroform). To give the title compound (34.17 g, 73%): TLC (20% ethyl acetate) / Chloroform) R_f  0.63; c) 3- [N- (tert-butoxycarbonyl) -N- (4-trifluoromethylbenzyl) a Minomethyl] -4-bromoanisole   3- [N- (4-trifluoromethylbenzyl) aminomethyl] -4-bromoaniso (34.17 g, 91 mmol) in dry THF (100 mL). Di-tert-butyl carbonate (22 g, 101 mmol) was added. Argon reactants Stirred under for 18 h (vigorous gas evolution was observed). Concentration and silica gel Chromatography (5-10% ethyl acetate / hexane) gave a colorless oil To give the title compound (41.09 g, 95%): TLC (silica, 20% acetic acid) Ethyl / hexane) R_f  0.44; d) 2- [N- (tert-butoxycarbonyl) -N- (4-trifluoromethylbenzyl) a Minomethyl] -4-methoxycinnamic acid methyl ester   3- [N- (tert-butoxycarbonyl) -N- (4-trifluoromethylbenzyl) a Minomethyl] -4-bromoanisole (37.08 g, 78 mmol), acrylic acid Methyl (35 mL, 390 mmol), palladium acetate (0.88 g, 3.9 mmol) Mol), tri-o-tolylphosphine (2.38 g, 7.8 mol) and diisopro Pyrethylamine (31 mL, 178 mmol) in acetonitrile (200 mL) )) Deoxygenate the solution (repeated three cycles of vacuum / argon purge) It was then heated to reflux under argon (in an oil bath set at 80 ° C.). 6 hours later Palladium acetate (0.88 g, 3.9 mmol) and tri-o-tolylphosphine (2.38 g, 7.8 mol) was added and the reaction was stirred at reflux for another 18 hours . The reaction was concentrated to dryness and the residue was ethyl ether / petroleum ether (1: 1) (3 0 mL) and left for 4 hours. The gray precipitate was filtered off and a small amount of ethyl ether Le / petroleum ether (1: 1) (100 mL). Concentrate the orange-red filtrate and concentrate on silica gel. Purified by flash chromatography (15% ethyl acetate / hexane). Obtained The residue was dissolved in hexane and the mixture was left for several hours, then filtered to remove the yellow precipitate. Was removed. The filtrate was concentrated to give the title compound as a thick yellow oil (34.52 g, 92%). Obtained: TLC (silica gel, 20% ethyl acetate / hexane) R_f  0.45;e) 2- [N- (tert-butoxycarbonyl) -N- (4-trifluoromethylbenzyl) Aminomethyl] methyl 4-methoxydihydrocinnamate   To 10% Pd / C (5 g, 4.7 mmol, pre-wet with DMF) was added 2- [N- (tert-butoxycarbonyl) -N- (4-trifluoromethylbenzyl) aminomethyl ] Methyl 4-methoxycinnamate (34.52 g, 72 mmol) in methanol (10 (0 mL). The mixture is placed under hydrogen (50 psi) under a Parr apparatus. For 7 hours and then filtered through a bed of celite to remove the catalyst. Concentrate the filtrate Reduction afforded the title compound as a colorless oil (34.15 g, 98%): f) 2- [N- (tert-butoxycarbonyl) -N- (4-trifluoromethylbenzyl) Aminomethyl] -4-methoxydihydrocinnamic acid   2- [N- (tert-butoxycarbonyl) -N- (4-trifluorobenzyl) amino [Tyl] -4-methoxydihydrocinnamic acid (34.15 g, 71 mmol) in dioxane (150 mL) to a stirred solution in aqueous 1 N sodium hydroxide (85 mL, 85 mm Mol) was added. The cloudy reaction was stirred at room temperature for 4 hours. The homogeneous solution obtained Liquid Neutralize with 1N hydrochloric acid (85 mL, 85 mmol) and ethyl acetate (2 × 250 mL) Extracted. Wash the combined organic layers with brine (250 mL) and dry (magnesium sulfate). Nesium) and concentrated to give the title compound as a thick colorless oil (34.60 g, 100%) Obtained: TLC (95: 4: 1 chloroform / methanol / acetic acid) R_f  0.4 9; g) (R) -4-benzyl-2-oxazolidinonyl 2- [N- (tert-butoxycarbonyl) ) -N- (4-Trifluoromethylbenzyl) aminomethyl] -4-methoxydihydrosi Nannamid   2- [N- (tert-butoxycarbonyl) -N- (4-trifluoromethylbenzyl) a Minomethyl] -4-methoxydihydrocinnamic acid (34.60 g, 71 mmol) and Pyridine (6.9 mL, 85 mmol) in dry dichloromethane (200 mL) To a stirred solution under argon was added cyanuric fluoride (4.4 mL, 48 mmol). ) Was added via syringe. The reaction was stirred at room temperature for 4 hours. The richness obtained The fresh suspension was filtered through a bed of celite and a small amount of dry dichloromethane (50 mL) Rinsed. The colorless filtrate was poured into a separating funnel and washed with ice-cold water (500 mL) . Dry (magnesium sulfate) and concentrate to give impure oxyfluoride (34.7). (0 g, 100%), which was used without further purification.   Of (R) -4-benzyl-2-oxazolidinone (13.8 g, 78 mmol) To a stirred solution in dry THF (300 mL) at −78 ° C. under Lugon via syringe Solution of n-butyllithium in hexane (2.5 M, 30 mL, 75 mmol) Was added. The reaction was stirred at -78 ° C for 15 minutes, then the oxyfluoride (3 4.70 g (71 mmol) in dry THF (100 mL) via syringe And added. The reaction was stirred at -78 ° C for 1 hour and then saturated ammonium chloride And extracted with ethyl acetate (2 × 200 mL). Remove the combined organic layers (400 mL), dried (magnesium sulfate) and concentrated to dryness. Flash on silica gel Purify by chromatography (20% ethyl acetate / hexane) The title compound (40.34 g, 90%) was obtained as a colorless oil: TLC (20% acetic acid) Ethyl / hexane) R_f  0.21; h) (R) -4-benzyl-2-oxazolidinonyl 3- [2- [N- (tert-butoxycal Bonyl) -N- (4-trifluoromethylbenzyl) aminomethyl] -4-methoxyphen Nyl] -2- (S) -methoxycarbonylmethylpropionamide   (R) -4-benzyl-2-oxazolidinonyl 2- [N- (tert-butoxycarbonyl) -N- (4-trifluoromethylbenzyl) aminomethyl] -4-methoxydihydrocin Namide (40.30 g, 64 mmol) in dry THF at -78 ° C (300 m L) into a stirred solution of lithium bis (trimethylsilyl) amide (70 mL, THF (1 M in 70 mmol) was added via syringe. 30 minutes later, bromo Methyl acetate (30 mL, 317 mmol) was added via syringe. further After 30 minutes at −78 ° C., the reaction was warmed to −20 ° C. and stirred for another 6 hours. reaction The product was quenched with saturated ammonium chloride (400 mL) and ethyl acetate (2 × 20 0 mL). Wash the combined organic layers with brine (300 mL) and dry ( Magnesium sulfate) and concentrated to dryness. Flash chromatography on silica gel Purify by luffy (20% ethyl acetate / hexane) to give the title compound as a white solid. (38.62 g, 86%): HPLC (A1tex Ultrasphere^TM-Si 5μ, 2 0% ethyl acetate / hexane), still about 20% unalkylated starting material Were present. The crude reaction mixture was subjected to HPLC to give 90% DE of the reaction. i) (S) -8-methoxy-3-oxo-2- (4-trifluoromethylbenzyl) -2,3, 4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (R) -4-benzyl-2-oxazolidinonyl 3- [2- [N- (tert-butoxycarbo) Nyl) -N- (4-trifluoromethylbenzyl) aminomethyl] -4-methoxyphenyl ] -2- (S) -methoxycarbonylmethylpropionamide (38.0 g, 54 ml (Mol) in a stirred solution of THF (300 mL) and water (100 mL). Over 30 minutes, 30% hydrogen peroxide (18.9 mL) and lithium hydroxide A solution of monohydrate (2.3 g, 55 mmol) in water (62 mL) was added dropwise. That The cloudy solution was stirred at 0 ° C. for another hour. The resulting homogeneous solution is mixed with sodium sulfite. (34.3 g, 272 mmol) in water (175 mL) at 0 ° C. Reacted quickly and then with ice-cold solution of concentrated hydrochloric acid (35 mL) in water (150 mL) Acidified. The reaction was extracted with ethyl acetate (2 × 200 mL) and the combined organic layers were separated. Wash with brine (400 mL), dry (magnesium sulfate) and concentrate to dryness Was. The resulting residue was stirred at room temperature with 4.0 M hydrochloric acid / dioxane (400 m L) (slow gas evolution was observed). After 1 hour, concentrate the reaction And concentrated again from chloroform / toluene (1; 1) (2x), then the residue ( 37.65 g) was dissolved in dry DMF (400 mL). 0 ° C, under argon To the stirred solution in the Dewar flask was added triethylamine (15.3 mL, 109 Mmol) and sodium bicarbonate (22.9 g, 273 mmol) This was followed by the addition of diphenylphosphoryl azide (13 mL, 60 mmol). 0 The reaction was concentrated to dryness by stirring at 24 ° C. for 24 hours. The residue was treated with ethyl acetate (400 m L) and washed successively with water (300 mL) and brine (300 mL) did. Dry (magnesium sulfate), concentrate and flash chromatograph on silica gel. As a colorless thick oil, subjected to chromatography (35% ethyl acetate / hexane) The title compound (16.87 g, 74%) was obtained: TLC (40% ethyl acetate / hex) Sun) R_f  0.50; MS (ES) m / e 422.3 (M + H)⁺; j) (S) -8-Hydroxy-3-oxo-2- (4-trifluoromethylbenzyl) -2, Methyl 3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   Boron tribromide solution in dichloromethane (1.0 M, 160 mL, 160 mM (S) -8-Methoxy-3-oxo-2- (4-trifluoro) over 30 minutes. (Romethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar Methyl chloride (16.67 g, 39.6 mmol) in anhydrous dichloromethane (150 mL) ) Was dropped into the solution at -20 ° C under argon. At -15 to -20 ° C After 1.5 hours, the reaction was cooled again to -20 ° C and methanol (160m L) was quenched by careful dropwise addition. The reaction is heated at -10 ° C to 0 ° C for 1 hour. Stirred for an hour and then concentrated on a rotary evaporator. Residue in methanol ( x2) and concentrated again. Flash chromatography on silica gel (50 To 100% ethyl acetate / hexane) to give the title compound as a white solid. (14.87 g, 92%): [α]_D-81.8 ° (c, 1.0, methanol) TLC (silica, 50% ethyl acetate / hexane) R_f  0.54; MS (ES) m / e 408.2 (M + H)⁺; Preparation Example 19 ( ±) -8-Methoxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5- HPLC analysis of enantiomers of methyl tetrahydro-2-benzazepine-4-acetate Separation a) (R)-(+)-8-Methoxy-3-oxo-2- (2,2,2-trifluoroethyl) -2, Methyl 3,4,5-tetrahydro-2-benzazepine-4-acetate and (S)-(−)-8- Methoxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahi Dro-2-benzazepine-4-methyl acetate   (±) -8-methoxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4, Methyl 5-tetrahydro-2-benzazepine-4-acetate was prepared using the following conditions: Resolved into its enantiomers by Ral HPLC: Diacel Chira1cel OJ (registered) Trademark) column (21.2 x 250 mm), methanol mobile phase, flow rate 15 mL / min , UV detection (295 nm), injection amount 400 mg; (R)-(+)-8-methoxy-3-o Oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-2-benz T for azepine-4-methyl acetate_RIs 4.9 minutes and (S)-(−)-8-methoxy C-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro- T for 2-benzazepine-4-methyl acetate_RIs 6.6 minutes.                                Preparation Example 20 ( ±) -8-hydroxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4, HPL of the enantiomer of methyl 5-tetrahydro-2-benzazepine-4-acetate C separation a) (R)-(+)-8-Hydroxy-3-oxo-2- (2,2,2-trifluoroethyl)- 2,3,4,5-tetrahydro-2-benzazepine-4-methyl acetate and (S)-(−)- 8-Hydroxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-te Trahydro-2-benzazepine-4-methyl acetate   (±) -8-Hydroxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4 Methyl 5,5-tetrahydro-2-benzazepine-4-acetate was prepared using the following conditions: Separation into its enantiomers by Ral HPLC: Diacel Chiralcel OD (registered Trademark) column (21.2 x 250 mm), 20% ethanol in hexane mobile phase, Flow rate 10 mL / min, UV detection (254 nm), injection volume 100 mg; (R)-(+)-8-Hydroxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3 For 4,4,5-tetrahydro-2-benzazepine-4-methyl acetate_RIs 14. 4 minutes and (S)-(−)-8-hydroxy-3-oxo-2- (2,2,2-trifluoro ethyl)- T for methyl 2,3,4,5-tetrahydro-2-benzazepine-4-acetate_RIs 18.5 minutes.                                Preparation Example 21 (S) -8-Hydroxy-3-oxo-2- (2,2,2) via enantioselective synthesis 2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine- Preparation of 4-methyl acetate a) 4-bromo-3-bromomethylanisole   Dried dichloromethane with 4-bromo-3-methylanisole (100 g, 497 mmol) N-bromosuccinimide (97 g, 5 g) was added to a stirred solution in dichloromethane (500 mL). 45 mmol) followed by benzoyl peroxide (6 g, 25 mmol). Was. The reactants were placed 150 inches with a reflector placed approximately 12 inches away from the reaction flask. Gently refluxed using a watt flood lamp. After 24 hours, the reaction is The volume was reduced to half with a rotary evaporator and allowed to stand for 4 hours. Formation The white precipitate formed was filtered off and rinsed with a small amount of dichloromethane. Concentrate and dry the filtrate And the remaining solid was triturated with hexane and filtered. Dry under vacuum To give the title compound as white needles (100.25 g, 72%): GCt_R= 6. 56 minutes (HP 530 μm × 20 m methyl silicone column, helium carrier -Flow rate 20 mL / min, initial temperature 100 ° C, initial time for 1 minute, 10 ° C / min speed, Final temperature 200 ° C., 1 minute final time); b) 3- [N- (2,2,2-trifluoroethyl) aminomethyl] -4-bromoaniso Le   222-trifluoroethylamine (24 g, 242 mmol) was added to 4-bromo- 3-Bromomethylanisole (33.6 g, 120 mmol) in anhydrous DMS0 (1 (25 mL) in a stirred solution at room temperature. Approximately 30-35 ° C Was heated. After stirring for 18 hours, the reaction was cooled with ice cold 1 N sodium hydroxide (200 mL) and extracted with ethyl ether (2 × 300 mL). Combined organic layers The brine (300 mL), dried (magnesium sulfate) and concentrated to a pale yellow oil. To give the title compound (41.35 g, 96%): TLC (toluene) R_f  0. 32; c) 3- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) a Minomethyl] -4-bromoanisole   3- [N- (2,2,2-trifluoroethyl) aminomethyl] -4-bromoanisole ( 41.35 g, 137 mmol) were added to di-tert-butyl dicarbonate (36 g, 165 mmol). Mol, liquefied by heating in a hot water bath). React the reaction with a small amount of (〜20 mL) and stirred in a 50 ° C. oil bath for 18 hours under argon (Slow gas evolution was observed). Concentrate on a rotary evaporator under vacuum After that, the obtained residue was diluted with hexane (100 mL) and a small amount of pure solid was added to the solution. Product (silica gel chromatography using 10% ethyl acetate / hexane as eluent) (Obtained from the preliminary reaction by chromatography). Mix the mixture for several hours at room temperature It was left and then placed in the refrigerator overnight. The product is collected by suction filtration and washed with hexane did. Drying under vacuum gave the title compound as a colorless solid: TLC (10% acetic acid Ethyl / toluene) R_f 0.52; d) 2- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) a Minomethyl] -4-methoxycinnamic acid methyl ester   3- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) amido Nomethyl] -4-bromoanisole (48.19 g, 121 mmol), acrylic acid Methyl (55 mL, 605 mmol), palladium acetate (1.36 g, 6.1 mmol) Mol), tri-o-tolylphosphine (3.69 g, 12 mol) and diisopro Pyrethylamine (49 mL, 278 mmol) in acetonitrile (200 mL) ) Remove the solution in Oxygenation (repeated 3 cycles of vacuum / argon purge) And heated to reflux in an oil bath set at 80 ° C. After 6 o'clock, add more palladium acetate (1.36 g, 6.1 mmol) and tri-o-tolylphosphine (3.69). g, 12 mol) and the reaction was stirred at reflux for a further 18 hours. Concentrate the reaction The residue was dissolved in ethyl ether / petroleum ether (1: 1) (30 mL). It was left for 4 hours. The gray precipitate was filtered off and a small amount of ethyl ether / petroleum Washed with Tell (1: 1) (） 100 mL). The orange-red filtrate is concentrated and By flash chromatography on Rica gel (15% ethyl acetate / hexane) Purified. The residue obtained was dissolved in hexane, the mixture was left for 2 hours and then filtered. Over time, a yellow precipitate was removed. The filtrate was concentrated to give the title compound as a yellow oil (45.85). g, 94%): TLC (20% ethyl acetate / hexane) R_f  0.50; e) 2- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) a Minomethyl] -4-methoxydihydrocinnamate   To 10% Pd / C (5 g, 4.7 mmol, pre-wet with DMF) was added 2- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) amino] methyl- Methyl 4-methoxycinnamate (45.85 g, 113 mmol) in methanol (10 (0 mL). The mixture is placed on a parser under hydrogen (50 psi) for 6 hours Shake and then filter through a bed of celite to remove the catalyst. Concentrate the filtrate to This gave the title compound (43.71 g, 95%) as a colored oil:f) 2- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) a Mi Nomethyl] -4-methoxydihydrocinnamic acid   2- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) amido Nomethyl] -4-methoxydihydrocinnamate (43.71 g, 108 mmol) To a stirred solution of dioxane (200 mL) in aqueous 1N sodium hydroxide (130 mL). mL, 130 mmol). The cloudy reaction was stirred at room temperature for 4 hours. The resulting homogeneous solution was neutralized with 1N hydrochloric acid (130 mL, 130 mmol) and acetic acid Extracted with ethyl (2 × 250 mL). Combine the organic layers with brine (250 mL) And dried (magnesium sulfate) and concentrated to give the title compound as a thick colorless oil ( 45.01 g, 100%): TLC (95: 4: 1 chloroform / meta) (Knol / acetic acid) R_f  0.49. g) (R) -4-benzyl-2-oxazolidinonyl 2- [N- (tert-butoxycarbonyl) ) -N- (2,2,2-trifluoroethyl) aminomethyl] -4-methoxydihydrocin Namid   2- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) amido Nomethyl] -4-methoxydihydrocinnamic acid (45.0 g, 108 mmol) and Lysine (10 mL, 124 mmol) in dry dichloromethane (400 mL) To a stirred solution under argon, add cyanuric acid fluoride (6.8 mL, 74 mmol) Was added via syringe. The reaction was stirred at room temperature for 4 hours. Obtained rich The suspension was filtered through a bed of celite, and the bed was filtered with a small amount of dry dichloromethane ( (50 mL). The colorless filtrate is poured into a separating funnel and ice-cold water (750 mL) And washed. Dry (magnesium sulphate) and concentrated, impure oxyfluoride (43.32 g, 100%), which was used without further purification.   Alcohol of (R) -4-benzyl-2-oxazolidinone (21 g, 119 mmol) To a stirred solution in dry THF (400 mL) at −78 ° C. under a syringe, via syringe A solution of n-butyllithium in hexane (2.5 M, 113 mmol) was added. . The reaction was stirred at -78 ° C for 15 minutes, then the oxyfluoride described above (43.32 g) ) 108 mmol) in dry THF (100 mL) is added via syringe did. reaction The material was stirred at -78 ° C for 1 hour, then quenched with saturated ammonium chloride, Extracted with ethyl (2 × 200 mL). Combine organic layers with brine (500 mL) , Dried (magnesium sulfate) and concentrated to dryness. Fra on silica gel Purification by flash chromatography (20% ethyl acetate / hexane) The title compound (55.27 g, 91%) was obtained as a clear colorless oil: TLC (silica, 20% ethyl acetate / hexane) R_f  0.24; h) (R) -4-benzyl-2-oxazolidinonyl 3- [2- [N- (tert-butoxycal Bonyl) -N- (2,2,2-trifluoroethyl) aminomethyl] -4-methoxyphenyl Ru] -2- (S) -Methoxycarbonylmethylpropionamide   (R) -4-benzyl-2-oxazolidinonyl 2- [N- (tert-butoxycarbonyl) -N- (2,2,2-trifluoroethyl) aminomethyl] -4-methoxydihydrocinna Mide (55.2 g, 100 mmol) in dry THF at -78 C (300 mL) ), Add lithium bis (trimethylsilyl) amide (115 mL, THF (1M in, 115 mmol) was added via syringe. 30 minutes later, bro Methyl moacetate (47 mL, 497 mmol) was added via syringe. Further After 30 minutes at −78 ° C., warm the reaction to −20 ° C. and stir for an additional 6 hours did. Quench the reaction with saturated ammonium chloride (400 mL) and add ethyl acetate (2 × 250 mL). Wash the combined organic layers with brine (400 mL) The mixture was dried (magnesium sulfate) and concentrated to dryness. Flash on silica gel Purify by chromatography (20% ethyl acetate / hexane) to give a white solid Of the title compound (52.44 g, 75%): HPLC (Altex Ultrasphere^TM -Si 5μ, 20% ethyl acetate / hexane), still about 6-7% unalkyl Starting material was present. The crude reaction mixture was subjected to HPLC to give 86% of the reaction DE was obtained. i) (S) -8-Methoxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4 , 5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (R) -4-benzyl-2-oxazolidinonyl 3- [2- [N- (tert-butoxycarbo) Nyl) -N- (2,2,2-trifluoroethyl) aminomethyl] -4-methoxyphenyl] -2- (S) -methoxycarbonylmethylpropionamide (52.40 g, 75 mm Mol) in THF (300 mL) and water (100 mL). Over 30 minutes, 30% hydrogen peroxide (26 mL) and lithium hydroxide monohydrate (3.2 g, 75 mmol) in water (85 mL) was added dropwise. Its cloudy solution The solution was stirred at 0 ° C. for another hour. The obtained homogeneous solution is mixed with sodium sulfite ( 46 g, 365 mmol) in water (240 mL) at 0 ° C. And then acidified with an ice-cold solution of concentrated hydrochloric acid (45 mL) in water (200 mL) . The reaction was extracted with ethyl acetate (2 × 300 mL) and the combined organic layers were washed with brine ( (600 mL), dried (magnesium sulfate) and concentrated to dryness. Obtained The resulting residue was reacted with 4.0 M hydrochloric acid / dioxane (500 mL) while stirring at room temperature. (Slow gas evolution was observed). After 1 hour, the reaction was concentrated and chloro Reconcentration from form / toluene (1; 1) (2x), then the residue (48.89) g) was dissolved in dry DMF (500 mL). This Dewa at 0 ° C under argon r To the stirred solution in the flask, add triethylamine (21 mL, 150 mmol) And sodium hydrogen carbonate (31.5 g, 375 mmol), followed by diphthene. Add phenyl phosphoryl azide (18 mL, 83.5 mmol). 24 at 0 ° C After stirring for an hour, the reaction was concentrated to dryness. Dissolve the residue in ethyl acetate (500 mL) It was then washed sequentially with water (400 mL) and brine (400 mL). Dry Dry (magnesium sulfate), concentrate and flash chromatograph on silica gel. (30% ethyl acetate / hexane) to give the title compound (2 1.81 g, 84%): [α]_D−132.6 ° (c, 1.0, methanol); TLC (40% ethyl acetate / hexane) R_f  0.56; Chiral HPLC (Chiracel OD, 20% ethanol / hexane) k '= 2.05; The enantiomer opposite the racemic standard had k '= 1.86 (not detected) MS (ES) m / e 346.2 (M + H)⁺; j) (S) -8-Hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H -2-Benzazepine-4-methyl acetate   Boron tribromide solution in dichloromethane (1.0 M, 250 mL, 250 mM (S) -8-methoxy-3-oxo-2- (2,2,2-triene) over 30 minutes. Fluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Methyl (21.5 g, 62.3 mmol) in anhydrous dichloromethane (230 mL) It was added dropwise to the solution at -20 ° C under argon. 1.5 more at -15 to -20 ° C After time, the reaction was re-cooled to −20 ° C. and methanol (250 mL) was added. Quenched by careful dripping. The reaction was stirred at -10 ° C to 0 ° C for 1 hour. The mixture was stirred and then concentrated on a rotary evaporator. Residue is methanol (x2) More concentrated again. Flash chromatography on silica gel (50% acetic acid The residue was purified by subjecting the title compound to a white solid (19.38 g, 9 4%): [α]_D-130.5 ° (c1.0, methanol); TLC (silica F, 40% ethyl acetate / hexane) R_f  0.40; MS (ES) m / e 332.1 (M + H)⁺; Preparation Example 22 (S) -8-Hydroxy-3-oxo-2- (2-fe) via enantioselective synthesis Nylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester Le a) 3- [N- (tert-butoxycarbonyl) -N- (2-phenylethyl) amino] methyl -4-Bromoanisole   2-phenethylamine (19.0 mL, 150 mmol) was added to 4-bromo-3-butane. Lomomethylanisole (14.0 g, 50.0 mmol) in anhydrous THF (200 m During L), they were added all at once to the solution at room temperature. After 18 hours, the mixture is Concentrated. Dissolve the residue in 2M sodium hydroxide (300 mL) and add (3 × 200 mL). Combine dichloromethane layer with magnesium sulfate And concentrated. Using 50% ethyl acetate / hexane as eluent And filtered through a plug of silica gel. The filtrate was concentrated under reduced pressure to give a yellow oil: MS (ES) m / e320 (M + H)⁺.   The above yellow oil was dissolved in anhydrous THF (200 mL) and di-tert-butyl dicarbonate ( (13.0 g, 60.0 mmol) were added all at once at room temperature. After one hour, the solution The liquid was concentrated. Flash silica gel chromatography (10% ethyl acetate / Hexane) to give the title compound (20.8 g, 4-bromo-3-butane) as an off-white solid. 100%) from lomomethylanisole.b) 4- [2- [N- (tert-butoxycarbonyl) -N- (2-phenylethyl) amino] me Tyl-4-methoxyphenyl] propionic acid   3- [N- (tert-butoxycarbonyl) -N- (2-phenylethyl) amino] methyl- 4-bromoanisole (20.0 g, 48.0 mmol), benzyl acrylate ( 23.0 g, 144 mmol), palladium acetate (540 mg, 2.40 mmol) ), Tri-o-tolylphosphine (1.46 g, 4.80 mmol) and diisopropane Ropilue Propionitrile (250 mL) of tylamine (17.0 mL, 96.0 mmol) )) Deoxygenate the solution (repeated three cycles of vacuum / argon purge) Then, it was heated and refluxed under argon. After 48 hours, the reaction was cooled to room temperature and It was filtered through a bed and concentrated. Flash silica gel chromatography (1 (0% ethyl acetate / hexane) to give a yellow oil which was added to 10% ethyl acetate / hexane. Dissolved in xane (100 mL) and left at 4 ° C. for 72 hours. Filter yellow precipitate for filtration And then the solution was concentrated to a slightly yellow oil (14.98 g, 62% ) Got.   Dissolve the above oil in methanol (150 mL) and add 10% Pd / C (6.40 g). , 6.00 mmol) at 0 ° C. The mixture was warmed to 0 ° C. and hydrogen (50 ps Shake under i) for 7 hours and then filtered through a bed of celite to remove the catalyst. Filtration Concentrate the liquid under reduced pressure to give the title compound as a thick yellow oil (10.35 g, 83%) I gotc) [[5-Methoxy-2- [3-oxo-3- [2-oxo-4- (phenylmethyl) -3-o] Xazolidinyl] propyl] phenyl] methyl] (2-phenylethyl) carbamic acid ( R) -1,1-dimethylethyl   4- [2- [N- (tert-butoxycarbonyl) -N- (2-phenylethyl) amino] methyl 2-Methoxyphenyl] propionic acid (10.35 g, 25.0 mmol) To a solution in chloromethane (125 mL) was added pyridine (2.4 mL, 30.0 mmol). ) And cyanuric acid fluoride (1.4 mL, 15.0 mmol) at room temperature. Added. After 2 hours, the mixture was filtered through a bed of celite and cold water (100 mL) Wash with brine (100 mL), dry over magnesium sulfate and concentrate Was.   (R) -4-benzyl-2-oxazolidinone (5.30 g, 30.0 mmol) water To a solution in THF (125 mL) at -78 ° C was added n-butyllithium (11.0 mL). , A 2.5 M solution in hexane, 27.5 mmol). After 15 passes, nothing The above oxyfluoride in water THF (25 mL) was added dropwise over 5 minutes. 1 o'clock After a short time, pour the mixture into water (300 mL) and extract with ethyl acetate (3 × 200 mL). Issued. The combined ethyl acetate layers were dried over magnesium sulfate and concentrated. Flash Silica gel chromatography (30% ethyl acetate / hexane) The title compound (12.12 g, 85%) was obtained as a neat oil: d) β-[[4-methoxy-2-[[[1,1-dimethylethoxy) carbonyl] (2-phenyl Ruethyl) amino] methyl] phenyl] methyl] -γ-oxo-4- (phenylmethyl) -3 -Oxazolidinebutanoic acid [R- (R *, S *)] methyl   [[5-Methoxy-2- [3-oxo-3- [2-oxo-4- (phenylmethyl) -3-oxo Sazolidinyl] propyl] phenyl] methyl] (2-phenylethyl) carbamic acid (R ) -1,1-Dimethylethyl (12.12 g, 21.0 mmol) in anhydrous THF (10. 0 mL) at −78 ° C. with lithium bis (trimethylsilyl) amide (22. (0 g, 1M in THF, 22.0 mmol) was added. 15 minutes later, bromoacetic acid Chill (9.9 mL, 105 mmol) was added and the mixture was warmed to -20 ° C did. After 3 hours, the mixture was poured into water (200 mL) and ethyl acetate (3 × 500 mL). The combined ethyl acetate layer was dried over magnesium sulfate and concentrated . Flash silica gel chromatography (25% ethyl acetate / hexane) To give the title compound and [[5-methoxy-2- [3-oxo-3- [2-oxo-4- (f Enylmethyl) -3-oxazolidinyl] propyl] phenyl] methyl] (2-phenyl Ethyl) (1,1) -dimethylethyl carbamate is each a 3: 2 mixture (H PLC, 20% ethyl acetate / hexane) (9.91 g). Further mix this mixture Used without purification: MS (ES) m / e 667 (M + Na)⁺. e) (S) -8-Methoxy-3-oxo-2- (2-phenylethyl) -2,3,4,5-tetra Hydro-1H-2-benzazepine-4-methyl acetate   β-[[4-methoxy-2-[[[1,1-dimethylethoxy) carbonyl] (2-phenyl Ethyl) amino] methyl] phenyl] methyl] -γ-oxo-4- (phenylmethyl) -3- [R- (R *, S *)] methyl oxazolidinebutanoate (9.91 g, 15.4 mmol) ) In THF (75 mL) was added lithium hydride monohydrate (646 mg, 15 mL). .4 mmol) and hydrogen peroxide (5.2 mL, 30% in water, 46.2 mmol) Of water in water (25 mL) was added at 0 ° C. over 10 minutes. 1.5 hours later, Add a solution of sodium sulfite (9.7 g, 77 mmol) in water (100 mL) did. The mixture was acidified to pH 4 using 2M hydrochloric acid and ethyl acetate (3x200m L). The combined ethyl acetate layers were dried over magnesium sulfate and concentrated. The resulting residue was dissolved in 4.0M hydrochloric acid in dioxane (75mL). 45 minutes later, The mixture was concentrated then reconcentrated from toluene (200 mL).   The above residue was dissolved in anhydrous DMF (75 mL). To this solution, add sodium bicarbonate Ium (6.50 g, 77.0 mmol) and triethylamine (4.3 mL. 30.8 mmol) at room temperature. The mixture is cooled to 0 ° C. Sphoryl azide (5 mL, 23.1 mmol) was added. After 16 hours, the mixture Was concentrated. Dissolve the obtained paste in ethyl acetate (500 mL) and add water (2 × (300 mL), dried over magnesium sulfate and concentrated. Flash series Kagel chromatography (40% ethyl acetate / hexane) to give the title compound (2.61 g, β-[[4-methoxy-2-[[[1,1-dimethylethoxy) carbonyl] (2 -Phenylethyl) amino] methyl] phenyl] methyl] -γ-oxo-4- (phenylmeth (R- (R *, S *)] methyl) -3-oxazolidinebutanoate (33% from methyl) Obtained as: MS (ES) m / e 390 (M + Na)⁺. f) (S) -8-Hydroxy-3-oxo-2- (2-phenylethyl) -2,3,4,5-tet Lahydro-1H-2-benzazepine-4-methyl acetate   (S) -8-methoxy-3-oxo-2- (2-phenylethyl) -2,3,4,5-tetrahi Do B-Dimethyl 2-H-2-benzazepine-4-acetate (2.61 g, 7.1 mmol) To a solution in chloromethane (40 mL) at −20 ° C. was added boron tribromide (21.3 mL, 1M solution in dichloromethane, 21.3 mmol) was added. 45 minutes later, the mixture Was quenched with methanol (200 mL) and concentrated. Silica gel plug for residue And filtered using 50% ethyl acetate / hexane as eluent. Got The orange solid was recrystallized from methanol / water to give the title compound (2.1) as an off-white solid. 6 g, 81%): MS (ES) m / e 376 (M + Na)⁺.                                 Example 1 ( ±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4,5- Preparation of tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-o Methyl oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide (1.4 g, 8 mmol) in anhydrous DMF (8 mL) was added to (±) -8-hydroxy-3-oxo. Methyl 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (1.7 g) , 7 mmol), triphenylphosphine (2.76 g, 11 mmol) and Diethyl azodicarboxylate (2.33 mL, 14 mmol) in anhydrous DMF (4 m L) and in THF (10 mL) was added dropwise to the solution under argon. Obtained The solution was stirred for 18 hours and then concentrated in vacuo. Silica gel chromatograph (2% -10% methanol / dichloromethane) to give the title compound (1.2 g) was obtained: MS (ES) m / e 400.2 (M + H).⁺. Unreacted (±) -8-hide Roxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Methyl (0.4 g) was also recovered. b) (±) -8- [3- (2-pyridylamino) -1-propyloxy] -3-oxo-2,3, 4,5-tetrahydro-1H-2-benzazepine-4-ethyl acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo Saw Methyl 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (1.2 g, 3 mmol), 10% palladium / activated carbon (1.2 g), cyclohexene (3 mL) , 15 mmol) and ethanol (20 mL) was heated at reflux for 18 hours. Was. The mixture was filtered and the filtrate was concentrated. The residue is chromatographed on silica gel. -(2% -5% methanol / dichloromethane) for purification as a white foam The title compound (0.72 g, 64%) was obtained: MS (ES) m / e 398.2 (M + H)⁺. c) (±) -8- [3- (2-pyridylamino) -1-propyloxy] -3-oxo-2,3,4 , 5-Tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, Ethyl 5-tetrahydro-1H-2-benzazepine-4-acetate (0.7 g, 2 mmol ), Lithium hydroxide monohydrate (0.12 g, 3 mmol), THF (5 mL), water (5 mL) and methanol (2 mL) was stirred at room temperature for 18 hours. And concentrated. The residue was partitioned between ethyl acetate and water, and the layers were separated. The aqueous phase is 3N salt The mixture was carefully adjusted to pH 4 with an acid and allowed to stand. The resulting catalyst was collected by filtration to give a tan solid. Obtained the title compound (0.4 g, 65%): MS m / e 370.4 (M + H).⁺; Yuan Elementary analysis: C₂₀H_{twenty three}N_ThreeO_Four・ 0.25H_TwoCalculated as O (%); C, 64.25; H, 6.34; N, 11.24; measured value (%); C, 64.02; H, 6.37; N, 1 1.20.                                 Example 2 ( ±) -8- [3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3-oxo Preparation of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -8- [3- [2- (4-nitro-N-oxopyridyl) amino] -1-propyloxy [S] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Chill   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide Using-[(3-hydroxy-1-propyl) amino] -4-nitropyridine-N-oxide The title compound was prepared as an orange foam following the procedure of Example 1 (a) except that Done: MS (ES) m / e 445.2 (M + H)⁺. b) (±) -8- [3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3-o Methyl oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo Instead of methyl so-2,3,4,5-tetrahydro-2-benzazepine-4-acetate (± ) -8- [3- [2- (4-Nitro-N-oxopyridyl) amino] -1-propyloxy] -3- Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate Except that the title compound was prepared as a white foam according to the procedure of Example 1 (b). MS: (ES) m / e 399.3 (M + H)⁺. c) (±) -8- [3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3-o Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -8- [instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate 3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3-oxo-2,3,4 Performed except using methyl 5,5-tetrahydro-1H-2-benzazepine-4-acetate Following the procedure of Example 1 (c), the title compound was prepared as a white foam: MS (E S) m / e 385.4 (M + H)⁺; Elemental analysis: C₂₀H_{twenty four}N_FourO_Four・ 1.25H_TwoO Calculated value (%); C, 59.03; H, 6.56; N, 13.76; Measurement value (% C, 58.80; H, 6.49; N, 13.62.                                 Example 3 ( ±) -8- [3-[(4-Methoxy-2-pyridyl) amino] -1-propyloxy] -3-oxo Preparation of So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -8- [3- [2- (4-Methoxy-N-oxopyridyl) amino] -1-propylthio [Xy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Methyl   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide - Using [(3-hydroxy-1-propyl) amino] -4-methoxypyridine-N-oxide The title compound was prepared as a colorless oil according to the procedure of Example 1 (a), except that : MS (ES) m / e 430.3 (M + H)⁺. b) (±) -8- [3-[(4-Methoxy-2-pyridyl) amino] -1-propyloxy] -3- Methyl oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -8- [3- [2- (4-Methoxy-N-oxopyridyl) amino] -1-propyloxy [S] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid The title compound was converted to a pale yellow oil according to the procedure of Example 1 (b) except using chill. MS (ES) m / e 414.4 (M + H)⁺. c) (±) -8- [3-[(4-Methoxy-2-pyridyl) amino] -1-propyloxy] -3- Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -8- [instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate 3-[(4-methoxy-2-pyridyl) amino] -1-propyloxy] -3-oxo-2,3, Other than using methyl 4,5-tetrahydro-1H-2-benzazepine-4-acetate, Following the procedure of Example 1 (c), the title compound was prepared as an off-white solid: MS ( ES) m / e 400.3 (M + H)⁺; Elemental analysis: C_{twenty one}H_{twenty five}N_ThreeO_Five・ 0.75H_Two O, calculated (%); C, 61.08; H, 6.47; N, 10.18; measured ( %); C, 61.15; H, 6.20; N, 10.12.                                 Example 4 ( ±) -8- [3- (2-Pyridylamino) -1-propyloxy] -2-methyl-3-oxo- Preparation of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -2-me H 3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester Le   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide (252.3 mg, 1.5 mmol) and diethyl azodicarboxylate (0.24 mL, 1.5 (Mmol) in anhydrous DMF (7.5 mL) at room temperature (±) -8-hydroxy-2. -Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar Methylate (197.5 mg, 0.75 mmol) and triphenylphosphine ( Slowly to a solution of 413.1 mg, 1.58 mmol) in anhydrous DMF (7.5 mL) It dripped dripping. It took 15 minutes for the dropwise addition, and the mixture slowly generated heat. After 2 hours, remove the reaction Concentrated and the residue was concentrated again from xylene. Silica gel chromatography (2 : 2: 1 ethyl acetate / chloroform / methanol), cloudy and almost colorless oil As R_f 0.48 (T of 2: 2: 1 ethyl acetate / chloroform / methanol LC). This material is again chromatographed on silica gel (no Water ethanol) to give the title compound as an off-white foam (243.9 mg, 79 %): TLC (absolute ethanol) R_f 0.33;b) (±) -8- [3- (2-pyridylamino) -1-propyloxy] -2-methyl-3-oxo Methyl so-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -2-methyl 3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester (243.9 mg, 0.59 mmol), cyclohexene (0.60 mL, 5.9 ml) Lmol) and 10% Pd / C (63 mg, 0.06 mmol) in 2-propanol (6 mL) was heated to reflux. After 21.5 hours, the reaction was cooled to room temperature, Through Celite And filtered. The filtrate was concentrated and the residue was concentrated again from toluene. Silica gel Chromatography (5% methanol in ethyl acetate / chloroform (1: 1)) To give the title compound (212.8 mg, 91%) as a colorless oil; TLC (vinegar Ethyl acid / 5% methanol in chloroform (1: 1) R_f 0.39; c) (±) -8- [3- (2-pyridylamino) -1-propyloxy] -2-methyl-3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   1.0 N lithium hydroxide (0.80 mL, 0.80 mmol) was added at room temperature to (±) -8. -[3- (2-Pyridylamino) -1-propyloxy] -2-methyl-3-oxo-2,3,4 , 5-Tetrahydro-1H-2-benzazepine-4-methyl acetate (207.5 mg, 0 (52 mmol) in THF (2.6 mL) and water (1.8 mL). Was. The initially cloudy solution became homogeneous within one minute. After 18 hours, the reaction was washed with TF Acidified with A (0.12 mL, 1.56 mmol) and concentrated. ODS chromatograph (20% acetonitrile / water containing 0.1% TFA), concentrated and lyophilized Drying gave the title compound (252.4 mg, 83%) as a light yellow hygroscopic solid: HPLC (PRP-1®, 20% acetonitrile with 0.1% TFA) / Water) K '= 2.4; MS (ES) m / e 384 (M + H)⁺; Elemental analysis: C_{twenty one}H_{twenty five}N_ThreeO_Four・ 1.5C F_ThreeCO_TwoH, calculated (%); C, 49.57; H, 5.11; N, 7.23; Fixed value (%); C, 49.65; H, 4.95; N, 7.15.                                 Example 5 ( ±) -8- [3- (2-imidazolylamino) -1-propyloxy] -3-oxo-2,3, Preparation of 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   The title compound is prepared almost according to the procedure described in Examples 1-4.                                 Example 6 ( ±) -8- [3- [2- (1,4,5,6-tetrahydropyrimidinyl) amino] -1-propyi Ruoxy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4- Preparation of acetic acid a) (±) -8- [3- (tert-butoxycarbonylamino) -1-propyloxy] -3-o Methyl oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   3-[(tert-butoxycarbonyl) amino] -1-propanol (0.14 g, 0.8 Mmol) and diethyl azodicarboxylate (0.13 mL, 0.8 mmol). The solution in anhydrous DMF (2 mL) was added to (±) -8-hydroxy-3-O at room temperature under argon. Methyl oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0. 10 g, 0.4 mmol) and triphenylphosphine (0.21 g, 0.8 mmol). Solution) in anhydrous DMF (1.4 mL) and dry THF (2 mL) did. The resulting solution was stirred for 18 hours and then concentrated under vacuum. Silica gel Chromatography (1% -3% methanol / dichloromethane) (0.11 g): MS (ES) m / e 407.3 (M + H)⁺. b) (±) -8- (3-Amino-1-propyloxy) -3-oxo-2,3,4,5-tetrahi Dro-1H-2-benzazepine-4-acetate methyl trifluoroacetate   (±) -8- [3- (tert-butoxycarbonylamino) -1-propyloxy] -3-oxo Seo Methyl-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.70 g) in dichloromethane (7 mL) and TFA (2 mL) under argon The mixture was stirred at 0 ° C for 1 hour, and then concentrated to give the title compound as colorless glass crystals (0.75 g, 100%). MS (ES) m / e 321.4 (M + H)⁺. c) (±) -8- [3- (pyrimidin-2-ylamino) -1-propyloxy] -3-oxo Methyl so-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   (±) -8- (3-Amino-1-propyloxy) -3-oxo-2,3,4,5-tetrahydrido B-1H-2-Benzazepine-4-acetic acid methyl trifluoroacetate (0.75 g, 2 mmol), 2-bromopyrimidine (0.5 g, 3 mmol), sodium hydrogen carbonate (1.4 g, 17 mmol) and ethanol (10 mL) heated Refluxed. After 24 hours, the mixture was filtered, and the insolubles were washed with methanol. Filtrate And the combined washings were concentrated and the residue was chromatographed on silica gel (1% -6% methanol / dichloromethane) and purified as white foam Compound (0.54 g, 82%) was obtained: MS (ES) m / e 385.5 (M + H).⁺ . d) (±) -8- [3-[(1,4,5,6-tetrahydropyrimidin-2-yl) amino] -1 -Propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepi N-4-acetic acid   (±) -8- [3- (Pyrimidin-2-ylamino) -1-propyloxy] -3-oxo-2 , 3,4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate (0.36 g, 0.94 mmol), 4M hydrochloric acid in dioxane (0.25 mL, 1 mmol), 10 % Palladium on activated carbon (0.24 g, 0.24 mmol) and methanol (5 m The mixture of L) was stirred under a hydrogen balloon. After 18 hours, the mixture was filtered and filtered. The liquid was concentrated. The residue was partitioned between ethyl acetate and aqueous potassium carbonate. Solids sink This was collected by filtration and dried to give the title compound as a white solid: MS (ES) m / e 375.4 (M + H)⁺. Elemental analysis: C₁₉H₂₆N_FourO_Four・ 2.5H_TwoAs O Calculated value (%); C, 54.40; H, 7.45; N, 13.35; Measured value (%); , 54.68; H, 7.12; N, 13.39.                                 Example 7 ( ±) -8- [3- (6-amino-2-pyridylamino) -1-propyloxy] -3-oxo- Preparation of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   The title compound is prepared almost according to the procedure described in Examples 1-4.                                 Example 8 ( ±) -8- [2- [6- (methylamino) pyridyl] ethoxy] -3-oxo-2,3,4,5- Preparation of tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo Methyl so-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   6 instead of 2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide The procedure of Example 1 (a), except using-(methylamino) -2-pyridylethanol To give the title compound as a white foam: MS (ES) m / e 384 ( M + H)⁺. b) (±) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -8- [instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate 2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo-2,3,4,5 Example 1 except that methyl-tetrahydro-1H-2-benzazepine-4-methylacetate was used The title compound was prepared as a white solid according to the procedure of (c): MS (ES) m / E 370 (M + H)⁺.                                 Example 9 ( ±) -8- [2- (2-Benzimidazolyl) ethoxy] -3-oxo-2,3,4,5-tetra Preparation of Lahydro-1H-2-benzazepine-4-acetic acid a) (±) -8- [2- (benzimidazol-2-yl) -1-ethoxy] -3-oxo-2, 3,4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide Example 1 (a) except that-(benzimidazol-2-yl) -1-ethanol was used The title compound was prepared as a white solid according to the procedure: MS (ES) m / e 394.4 (M + H)⁺, 416.3 (M + Na)⁺. b) (±) -8- [2- (benzimidazol-2-yl) -1-ethoxy] -3-oxo-2, 3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -8- [instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate 2- (benzimidazol-2-yl) -1-ethoxy] -3-oxo-2,3,4,5-tetra Example 1 (c), except that methyl lahydro-1H-2-benzazepine-4-acetate was used. The title compound was prepared as a white powder according to the procedure in ()): MS (ES) m / e  380.4 (M + H)⁺, 402.3 (M + Na)⁺.                                 Example 10 ( ±) -8- [2- (4-Aza-2-benzimidazolyl) ethoxy] -3-oxo-2,3,4 Preparation of 5-tetrahydro-1H-2-benzazepine-4-acetic acid   The title compound is prepared largely according to the procedure described in Example 9.                                 Example 11 ( ±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- (2 , 2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepi Preparation of N-4-acetic acid a) (±) -3-oxo-8- [3- (1-oxopyridin-2-ylamino) -1-propyl Oxy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H- 2-benzazepine-4-methyl acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide (252.3 mg, 1.5 mmol) and diethyl azodicarboxylate (0.24 mL, 1.5 Mmol) in anhydrous DMF (7.5 mL) was added to (±) -8-hydroxy-3-oxo. So-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-be Methyl nzazepine-4-acetate (248.5 g, 0.75 mmol) and triphenylene Luphosphine (413.1 mg, 1.58 mmol) in anhydrous DMF (7.5 mL) The solution was slowly dropped into the solution at room temperature over 3-4 minutes. 17 hours later, The reaction was concentrated and the residue was again concentrated from xylene / chloroform. Silica gel Chromatography (gradient: ethyl acetate (500 mL) followed by 5% methanol / Chloroform) to give the title compound (253.6 mg, 70%) as an off-white foam Got as: b) (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2 -(2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzyl Zepin-4-methyl acetate   (±) -3-oxo-8- [3- (1-oxopyridin-2-ylamino) -1-propylthio [Xy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2- Methyl benzazepine-4-acetate (253.6 mg, 0.53 mmol), cyclohexane Xen (0.54 mL, 5.3 mmol), palladium black (11.3 mg, 0.11 (Mmol) and isopropanol (5.3 mL) was heated to reflux. 0. After 5 hours, 10% Pd / C (28.2 mg, 0.03 mmol) was added and 14.5 hours After a period of time, palladium black (11.3 mg, 0.11 mmol) and cyclohexene (0.27 mL, 2.65 mmol) was added. After another 48 hours, The reaction was hot filtered through celite and the filter bed was washed with hot methanol / chloroform (1 : 1). Dark And concentrated again from xylene to give a yellow oil. Silica gel chromatography (5% methanol in ethyl acetate / chloroform (1: 1)) to give a light yellow oil To give the title compound (194.0 mg, 79%): TLC (ethyl acetate / chloroform) 5% methanol in form (1: 1) R_f 0.53; c) (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2 -(2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-acetic acid   1.0 N lithium hydroxide (0.44 mL, 0.44 mmol) was added at room temperature to (±) -8. -[3- (2-pyridylamino) -1-propyloxy] -2-methyl-3-oxo-2- (2, (2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepi Methyl 4-methyl acetate (159.5 mg, 0.34 mmol) in THF (1.7 mL) And a solution in water (1.3 mL). Yellow cloudy solution within 10 minutes It became homogeneous. After 24 hours, the reaction was concentrated to dryness and the yellow residue was taken up in water (4 mL). Melted. The solution was filtered and then carefully neutralized (pH ≒ 7) with 1.0N hydrochloric acid. . Collect the precipitate, wash with copious amounts of water, dry under high vacuum at 40-45 ° C and label Compound (130.0 mg, 83%) was obtained as an off-white solid: HPLC (PRP-1 (Registered trademark), 25% acetonitrile / water with 0.1% TFA) K '= 3.1; Elemental analysis: C_{twenty two}H_{twenty four}F_ThreeN_ThreeO_Four・ 0.5H_TwoCalculated value (%) as O; C, 57.3 9; H, 5.47; N, 9.12; found (%); C, 57.39; H, 5.18; N, 9.00.                                 Example 12 ( ±) -8- [3- (4,6-dimethylpyridin-2-ylamino) -1-propyloxy] -2 -Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar Preparation of acid a) (±) -8- [3- (4,6-dimethyl-1-oxopyridin-2-ylamino) -1-pro Pyroxy] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benz Azepine-4-methyl acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide -[(3-Hydroxy-1-propyl) amino] -4,6-dimethylpyridine-N-oxide The title compound was converted into a white foam according to the procedure of Example 1 (a) except using Prepared: MS (ES) m / e 442.3 (M + H)⁺. b) (±) -8- [3- (4,6-dimethylpyridin-2-ylamino) -1-propyloxy ] -2-Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4 -Methyl acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -8- [3- (4,6-dimethyl-1-oxopyridin-2-ylamino) -1-propy Roxy] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benza The title compound was prepared according to the procedure of Example 1 (b) except for using methyl sepin-4-acetate. Prepared as pale yellow solid: MS (ES) m / e 426.3 (M + H)⁺. c) (±) -8- [3- (4,6-dimethylpyridin-2-ylamino) -1-propyloxy ] -2-Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4 -Acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -8- [instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate 3-[(4,6-dimethylpyridin-2-yl) amino] -1-propyloxy] -2-methyl Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate The title compound was prepared as a white solid according to the procedure of Example 1 (c), except that Prepared: MS (ES) m / e 412.2 (M + H)⁺; Elemental analysis: C_{twenty three}H₂₉N_ThreeO_Four ・ 0.5HCl ・ 0.25H_TwoCalculated value (%) as O; C, 63.62; H, 6.9 6; N, 9.68; found (%); C, 63.62; H, 6.96; N, 9.69.                                 Example 13 ( ±) -8- [2- (2-Aminothiazol-4-yl) -1-ethoxy] -2-methyl-3-oxo Preparation of So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -8- [2- (2-Aminothiazol-4-yl) -1-ethoxy] -2-methyl-3-methyl Methyl oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide Using-(2-aminothiazol-4-yl) ethanol (WO95 / 32710) Otherwise, according to the procedure of Example 1 (a), the title compound was prepared as a white foam. : MS (ES) m / e 390 (M + H)⁺. b) (±) -8- [2- (2-aminothiazol-4-yl) -1-ethoxy] -2-methyl-3- Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -8- [instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate 2- (2-aminothiazol-4-yl) -1-ethoxy] -2-methyl-3-oxo-2,3, Other than using methyl 4,5-tetrahydro-1H-2-benzazepine-4-acetate, Example 1 The title compound was prepared as a white solid according to the procedure of (c): MS (ES) m / E 376 (M + H)⁺. Elemental analysis: C₁₈H_{twenty one}N_ThreeO_FourS 1.3CF_ThreeCO_TwoH 0.36H_TwoCalculated as O (%); C, 46.62; H, 4.38; N, 7.93; Found: (%); C, 46.45; H, 4.57; N, 8.27.                                 Example 14 ( ±) -8- [3- (4-Aminopyridin-2-ylamiha-1-propyloxy] -2-methyl Preparation of 3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Made a) (±) -8- [3- (4-Nitro-1-oxopyridin-2-ylamino) -1-propyl Oxy] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzaze Pin-4-methyl acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide -[(3-Hydroxy-1-propyl) amino] -4-nitropyridine-N-oxide is converted to ( ±) -8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzaze (±) -8-hydroxy-2-methyl-3-oxo-2,3 instead of pin-4-methyl acetate Except that methyl 4,4,5-tetrahydro-1H-2-benzazepine-4-acetate was used. The title compound was prepared according to the procedure of Example 1 (a): MS (ES) m / e 4 59 (M + H)⁺. b) (±) -8- [3- (4-aminopyridin-2-ylamino) -1-propyloxy] -2- Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Methyl   (±) -8- [3- (4-Nitro-N-oxopyridin-2-ylamino) -1-propylthio [Xy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid (±) -8- [3- (4-Nitro-1-oxopyridin-2-ylamino)-instead of methyl 1-propyloxy] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2- Following the procedure of Example 1 (b), but using benzazepine-4-methyl acetate, The title compound was prepared as a white foam: MS (ES) m / e 413 (M + H )⁺. c) (±) -8- [3- (4-aminopyridin-2-ylamino) -1-propyloxy] -2 -Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -8- [instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate 3- (4-aminopyridin-2-ylamino) -1-propyloxy] -2-methyl-3-o Using methyl oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate The title compound was prepared as a white solid according to the procedure of Example 1 (c), except that : MS (ES) m / e 399 (M + H)⁺. Elemental analysis: C_{twenty one}H₂₆N_FourO_Four・ 1.5 CF_ThreeCO_TwoH ・ 0.125H_TwoCalculated value (%) as O; C, 50.62; H, 4.9 1; N, 9.83; Found (%); C, 50.63; H, 5.26; N, 9.90.                                Example 15 ( ±) -8- [3- (pyrimidin-2-ylamino) -1-propyloxy] -3-oxo-2, Preparation of 3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (Pyrimidin-2-ylamino) -1-propyloxy] -3-oxo-2 Methyl 3,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.071 g , 0.18 mmol) and lithium hydroxide monohydrate (0.009 g, 2 mmol) ) In THF (5 mL) and water (2 mL) was stirred at room temperature for 18 h. And concentrated. The residue was dissolved in water and the pH was adjusted to 4 with 3N hydrochloric acid. Obtained solid The body was collected by filtration and dried to give the title compound (0.05g, 73%) as a white solid. Obtained: MS (ES) m / e 371.4 (M + H).⁺; Elemental analysis: C₁₉H_{twenty two}N_FourO_Four ・ 0.5H_TwoCalculated as O (%); C, 60.15; H, 6.11; N, 14.77. Measured value (%); C, 60.14; H, 6.06; N, 14.71.                                Example 16 ( R) -8- [3-[(4-Amino-2-pyridyl) amino] -1-propyloxy] -3-oxo Preparation of So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid a) (R) -8- [3- [2- (4-Nitro-1-oxopyridyl) amino] -1-propyloxy Shi]- Methyl 3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide Using-[(3-hydroxy-1-propyl) amino] -4-nitropyridine-N-oxide The title compound was prepared as an orange foam following the procedure of Example 1 (a), except that : MS (ES) m / e 445.3 (M + H)⁺. b) (R) -8- [3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3-o Methyl oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate To (R) -8- [3- [2- (4-amino-N-oxopyridyl) amino] -1-propyloxy ] -3-Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate The title compound was converted into a white foam according to the procedure of Example 1 (b), except that MS (ES) m / e 399.4 (M + H)⁺. c) (R) -8- [3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3- Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, Instead of ethyl 5-tetrahydro-1H-2-benzazepine-4-acetate, (R) -8- [ 3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3-oxo-2,3,4 Performed except using methyl 5,5-tetrahydro-1H-2-benzazepine-4-acetate Following the procedure of Example 1 (c), the title compound was prepared as an off-white solid: [Α]_D ^{twenty three}+ 74.97 ° (c 1.45, methanol); MS (ES) m / e 38 5.4 (M + H)⁺. Elemental analysis: C₂₀H_{twenty four}N_FourO_Four・ HCl 1.5H_TwoO Calculated value (%); C, 53.63; H, 6.30; N, 12.50; Measured value (%); C, 5 3.87; H, 6.13; N, 12.42.                                Example 17 ( S) -8- [3-[(4-Amino-2-pyridyl) amino] -1-propyloxy] -3-oxo Preparation of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid a) (S) -8- [3- [2- (4-nitro-N-oxopyridyl) amino] -1-propylthio [Xy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Methyl   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide Using-[(3-hydroxy-1-propyl) amino] -4-nitropyridine-N-oxide The title compound was prepared as an orange foam following the procedure of Example 1 (a), except that : MS (ES) m / e 445.3 (M + H)⁺. b) (S) -8- [3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3- Methyl oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate To (S) -8- [3- [2- (4-amino-N-oxopyridyl) amino] -1-propyloxy [S] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid The title compound was converted to a white foam according to the procedure of Example 1 (b) except using chill. MS (ES) m / e 399.4 (M + H)⁺. c) (S) -8- [3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3-o Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (S) -8- [instead of ethyl 5-tetrahydro-1H-2-benzazepine-4-acetate 3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3-oxo-2,3, Other than using methyl 4,5-tetrahydro-1H-2-benzazepine-4-acetate, Following the procedure of Example 1 (c), the title compound was prepared as an off-white solid: [Α]_D ^{twenty three}-77.5 ° (c 1.45, methanol); MS (ES) m / e 385 .4 (M + H)⁺. Elemental analysis: C₂₀H_{twenty four}N_FourO_Four・ 1.125H_TwoAs O, the calculated value ( %); C, 59.36; H, 6.54; N, 13.84; measured value (%); C, 59.31; 6.74; N, 13.73.                                Example 18 ( ±) -8- [3- (2-Pyridylamino) -1-propyloxy] -2-methyl-3-oxo- Preparation of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-ethyl acetate a) (±) -8- [3-[(4-amino-2-pyridyl) amino] -1-propyloxy] -3-o Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid (0.27 g , 0.7 mmol) and 4M hydrochloric acid in dioxane (0.2 mL, 0.8 mmol). The solution in ethanol (10 mL) was heated to reflux. After 72 hours, the reaction was concentrated, The residue was partitioned between ethyl acetate and aqueous potassium carbonate. Wash organic phase with brine It was dried (magnesium sulfate) and concentrated. The residue was washed with toluene (5 mL) and toluene. Dissolve in triethylamine (0.35 mL, 2.5 mmol) and heat the resulting solution Refluxed. After 18 hours, the reaction was concentrated in vacuo to give the title compound as a tan foam. (0.20 g, 69%): MS (ES) m / e 413.4 (M + H).⁺. Elemental analysis: C_{twenty two}H₂₈N_FourO_Four・ 0.25H_TwoCalculated value (%) as O; C, 63.37 H, 6.89; N, 13.44; Measurement (%); C, 63.32; H, 7.17; 13.05.                                Example 19 ( ±) -8- [3-[(2-Imidazolin-2-yl) amino] -1-propyloxy] -2-methyl Preparation of 3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Made a) (±) -8- [3- (4-nitrobenzyloxycarbonylamino) -1-propylthio [Xy] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepi Preparation of methyl-4-methyl acetate   Instead of 2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide, 3 -(4-Nitrobenzyloxycarbonylamino) -1-propanol is converted to (±) -8- Droxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar (±) -8-hydroxy-2-methyl-3-oxo-2,3,4,5-te Traffic Example 1 (a) except that dro-1H-2-benzazepine-4-methyl acetate was used. Following the procedure, the title compound was prepared as a colorless oil: MS (ES) m / e 50 0.3 (M + H)⁺. b) (±) -8- [3-Amino-1-propyloxy] -2-methyl-3-oxo-2,3,4, Methyl 5-tetrahydro-1H-2-benzazepine-4-acetate   (±) -8- [3- (4-nitrobenzyloxycarbonylamino) -1-propyloxy [S] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine- 4-Methyl acetate (1.4 g, 3 mmol), 10% palladium on activated carbon (0.55) g, 0.6 mmol) and ethanol (20 mL) with a hydrogen balloon Under stirring at room temperature. After 18 hours, the mixture was stirred and the filtrate was concentrated. The title compound (0.89 g, 99%) was obtained as a tan solid: MS (ES) m / e 321.4 (M + H)⁺. c) (±) -8- [3-[(2-imidazolin-2-yl) amino] -1-propyloxy] -2- Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Methyl   (±) -8- [3-Amino-1-propyloxy] -2-methyl-3-oxo-2,3,4,5- Methyl tetrahydro-1H-2-benzazepine-4-acetate (0.3 g, 1 mmol) 2,2-methylthioimidazoline (0.46 g, 2 mmol), diisopropylethyl Luamine (0.42 mL, 2 mmol) and dimethylacetamide (3 mL) Was heated to 100 ° C. under argon. After 2 hours, concentrate the reaction under vacuum And the residue was partitioned between chloroform and water. Dry the organic phase (magnesium sulfate ) And concentrated, and the residue was purified by preparative HPLC to afford the title compound (0.2 as a yellow oil). 4 g, 51%): MS (ES) m / e 389.1 (M + H).⁺. d) (±) -8- [3-[(2-imidazolin-2-yl) amino] -1-propyloxy] -2- Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3-[(2-Imidazolin-2-yl) amino] -1-propyloxy] -2-me Tyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid The chill was saponified according to the procedure of Example 1 (c). Purified by preparative HPLC To give the title compound as a white solid: MS (ES) m / e 375.4 (M + H )⁺. Elemental analysis: C_{twenty one}H₂₆N_FourO_Four・ 1.96CF_ThreeCO_TwoCalculated value (%) as H; C, 46.08; H, 4.73; N, 9.39; Found (%); C, 46.37; H, 4. 53; N, 9.01.                                Example 20 ( ±) -8- [3-[(4,5,6,7-tetrahydro-1H-2-diazepin-2-yl) amino ] -1-Propyloxy] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2 Preparation of 1-benzazepine-4-acetic acid a) (±) -8- [3-[(2-Diazepin-2-yl) amino] -1-propyloxy] -2-me Tyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Chill   Use 2-methylthio-1,3-diazepine instead of 2-methylthioimidazoline The title compound was prepared according to the procedure of Example 19 (c) except that S) m / e 417.4 (M + H)⁺. b) (±) -8- [3-[(2-Diazepin-2-yl) amino] -1-propyloxy] -2-me Tyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3-[(2-Imidazolin-2-yl) amino] -1-propyloxy] -2-me Tyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid (±) -8- [3-[(2-Diazepan-2-yl) amino] -1-propylthio [Xy] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepi The title compound was prepared according to the procedure of Example 19 (d) except for using methyl 4-acetate. Was prepared: MS (ES) m / e 403.4 (M + H).⁺.                                Example 21 ( ±) -3-oxo-8- [3- (4-methylpyridin-2-ylamino) -1-propyloxy [S] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-be Preparation of Ndazepine-4-acetic acid a) (±) -3-oxo-8- [3- (4-methyl-1-oxopyridin-2-ylamino)- 1-propyloxy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahi Dro-1H-2-benzazepine-4-methyl acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide -[(3-Hydroxy-1-propyl) amino] -4-methylpyridine-N-oxide is converted to ( ±) -8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzaze (±) -3-oxo-8-hydroxy-2- (2,2,2-to) instead of pin-4-methyl acetate (Lifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar The title compound was prepared according to the procedure of Example 1 (a) except using methyl acid. : MS (ES) m / e 496.3 (M + H)⁺. b) (±) -3-oxo-8- [3- (4-methylpyridin-2-ylamino) -1-propyl Oxy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H- 2-benzazepine-4-methyl acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -3-oxo-8- [3- (4-methyl-1-oxopyridin-2-ylamino) -1 -Propyloxy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydrido B) The procedure of Example 1 (b) was repeated except that 1H-2-benzazepine-4-methyl acetate was used. The title compound was prepared according to the procedure: MS (ES) m / e 480.2 (M + H).⁺ . c) (±) -3-oxo-8- [3- (4-methylpyridin-2-ylamino) -1-propylthio [Xy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2- Benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -3-O instead of methyl 5-tetrahydro-1H-2-benzazepine-4-acetate Xo-8- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] -2- (2, (2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepi The title compound was prepared according to the procedure of Example 1 (c) except using methyl 4-acetate. Prepared: MS (ES) m / e 466.2 (M + H)⁺. Elemental analysis: C_{twenty three}H₂₆F_Three N_ThreeO_Four・ 0.5H_TwoAs O, calculated value (%); C, 58.22; H, 5.74; N, 8. 86; found (%); C, 58.54; H, 5.58; N, 8.64.                                Example 22 ( ±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbonyl ) Amino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzaze Preparation of pin-4-acetic acid a) (±) -8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbonyl) amido [No] -1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benz Azepine-4-methyl acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarbonyl) L) amino] -1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H-2 According to the procedure of Example 1 (b), except that -benzazepine-4-methyl acetate is used. The title compound was prepared as a white foam: MS (ES) m / e 484.4 (M + H)⁺. b) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbo) Nil) amino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benz Azepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -8- [instead of methyl 5-tetrahydro-1H-2-benzazepine-4-acetate 3- [N- (pyridin-2-yl) -N- (tert-butoxycarbonyl) amino] -1-propyi Luo [Xy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid The title compound was converted to a white powder according to the procedure of Example 1 (c) except for using methyl. MS (ES) m / e 470.4 (M + H)⁺. Elemental analysis: C_{twenty five}H₃₀NaN_ThreeO₆・ 3.25H_TwoCalculated value (%) as O; C, 54. 59. H, 6.69; N, 7.64; found (%); C, 54.47; H, 6.32; N , 7.95.                                Example 23 ( ±) -8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarbonyl ) Amino] -1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H-2- Preparation of benzazepine-4-acetic acid a) (±) -8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarbo) Nyl) amino] -1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H- 2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -8- [instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate 3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarbonyl) amino]- 1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzaze The title compound was prepared according to the procedure of Example 1 (c) except using pin-4-methyl acetate. Was prepared as a white powder: Example 24 ( ±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbonyl ) Amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4, Preparation of 5-tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-but Ki [Cicarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) M) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate   (±) -8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarboni L) amino] -1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H-2 Methyl-benzazepine-4-acetate (0.4 g, 0.8 mmol) in DMF (5 mL) )) To -20 ° C. (carbon tetrachloride / dry ice bath) and (TMS)_TwoNL i (1.0 M solution in THF, 0.9 mL, 0.9 mmol) was added dropwise. 10 minutes later Of 4-trifluoromethylbenzyl bromide (0.211 g, 0.88 mmol) in D A solution in MF (0.5 mL) was added. The solution was heated at -20 ° C under an argon atmosphere. Stir for 10 minutes and then at room temperature for 18 hours. Concentrate the solution and dissolve in ethyl acetate But 5% sodium bicarbonate (2x), water (1x), 5% citric acid (2x), Washed sequentially with water (1x) and brine (1x). Dry the ethyl acetate layer ( Magnesium sulfate) and concentrated to give the title compound (0.42 g, 80%): M S (ES) m / e 658.3 (M + H)⁺. b) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbo) Nil) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, 4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo Instead of so-2,3,4,5-tetrahydro-2-benzazepine-4-ethyl acetate (± ) -3-Oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycal Bonyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2, Other than using methyl 3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, Following the procedure of Example 1 (b), the title compound was prepared as a colorless oil: MS (E S) m / e 642.3 (M + H)⁺. c) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbo) Nyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3 , 4, 5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -3-O instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate Xo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbonyl) amino]- 1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetra Example 1 (c) except that methyl hydro-1H-2-benzazepine-4-acetate is used The title compound was prepared as an off-white solid according to the procedure: MS (ES) m / e  628.4 (M + H)⁺. Elemental analysis: C₃₃H₃₆F_ThreeN_ThreeO₆・ 0.5H_TwoO Calculated value (%); C, 62.25; H, 5.86; N, 6.60; Measured value (%); 01; H, 5.92; N, 6.81.                                Example 25 ( ±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- (4 -Trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benzaze Preparation of pin-4-acetic acid a) (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2 -(4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benz Azepine-4-acetic acid   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, 4,5-Tetrahydro-1H-2-benzazepine-4-acetic acid (0.158 g, 0.25 Mmol) with 4 M hydrochloric acid in dioxane (3 mL) at room temperature for 1 hour. The solution was concentrated. ODS chromatography (gradient 5-60% acetonitrile / Water (containing 0.1% TFA) for more than 1 hour), concentrate, freeze-dry and The compound (0.117 g, 82%) was obtained: MS (ES) m / e 528.4 (M + H)⁺. Elemental analysis: C₂₈H₂₈N_ThreeO_Four・ CF_ThreeCO_TwoH 1.5H_TwoCalculated value as O (%); C, 53.89; H, 4.82; N, 6.28; measured value (%); C, 53.55. H, 4.55; N, 6.04.Example 26 ( ±) -2-Methyl-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (methyl) amino ] -1-Propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4- Preparation of acetic acid a) (±) -8- [3- [2- (N-oxopyridyl) -N- (methyl) amino] -1-propylthio [Xy] -3-oxo-2,3,4,5-tetrahydro-1H-2-methylbenzazepine-4 -Methyl acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo Sodium 2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (1.5 g) (3.8 mmol) in DMF (10 mL) at -20 ° C under an argon atmosphere. Cool, (TMS)_TwoNLi (1.0 M solution in THF, 8 mL, 8 mmol) was added dropwise. Was. The reaction was stirred at −20 ° C. for 30 minutes, then methyl iodide (0.5 mL, 7.5 mL). 6 mmol) was added. The solution was stirred at room temperature for 18 hours and then concentrated. Siri Labeled by Kagel chromatography (10% methanol / dichloromethane) The compound (1 g, 62%) was obtained: MS (ES) m / e 428.4 (M + H).⁺. b) (±) -2-methyl-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (methyl) a Mino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine -4-Methyl acetate   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) instead of 5-tetrahydro-1H-2-methylbenzazepine-4-ethyl acetate -8- [3- [2- (N-oxopyridyl) -N- (methyl) amino] -1-propyloxy] -3 -Oxo-2,3,4,5-tetrahydro-1H-2-methylbenzazepine-4-acetic acid The title compound was prepared according to the procedure of Example 1 (b) except using chill: M S (ES) m / e 412.4 (M + H)⁺. c) (±) -2-Methyl-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (methyl) a Mi [No] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine- 4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, Instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate, (±) -2-me Tyl-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (methyl) amino] -1-pro Pyroxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate The crude title compound was prepared according to the procedure of Example 1 (c), except using toluene. ODS chromatography (5-60% acetonitrile / water (containing 0.1% TFA) Yes, over 1 hour), concentrated and lyophilized to give the title compound: MS (E S) m / e 398.4 (M + H)⁺. Elemental analysis: C_{twenty two}H₂₇N_ThreeO_Four・ 1.5CF_ThreeCO_Two H ・ 0.25H_TwoAs O, calculated value (%); C, 52.40; H, 5.10; N, 7. 33; found (%); C, 52.09; H, 5.26; N, 7.20.                                Example 27 ( ±) -2-benzyl-3-oxo-8- [3- (pyridin-2-ylamino) -1-propylthio Preparation of [xy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -2-benzyl-3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N -(tert-Butoxycarbonyl) amino] -1-propyloxy] -2,3,4,5-tetra Hydro-1H-2-benzazepine-4-methyl acetate   Except that benzyl bromide is used instead of 4-trifluoromethylbenzyl bromide The title compound (0.105 g, 20%) was prepared according to the procedure of Example 24 (a). Done: MS (ES) m / e 590.4 (M + H)⁺. b) (±) -2-benzyl-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butyl) Toxycarbonyl) amino] -1-propyloxy] -2,3,4,5-tetrahydro-1 H-2-Benzazepine-4-methyl acetate   (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxy) [Cicarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -) Instead of methyl 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate ( ±) -2-benzyl-3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (ter t-butoxycarbonyl) amino] -1-propyloxy] -2,3,4,5-tetrahydro The procedure of Example 24 (b) was repeated except that -1H-2-benzazepine-4-methyl acetate was used. The title compound (0.045 g, 44%) was prepared according to the procedure: MS (ES) m / E 574.4 (M + H)⁺. c) (±) -2-benzyl-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butyl) Toxycarbonyl) amino] -1-propyloxy] -2,3,4,5-tetrahydro-1 H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, Instead of (5-tetrahydro-1H-2-benzazepine-4-ethyl acetate), (±) -2-be Benzyl-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benza The procedure of Example 1 (c) was repeated, except that methyl zepin-4-methyl acetate was used. (0.044 g, quant.): MS (ES) m / e 560.3 (M + H )⁺. d) (±) -2-benzyl-3-oxo-8- [3- (pyridin-2-ylamino) -1-propy Ruoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, (±) -2-Ben in place of 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Jil-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbonyl ) Amino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzaze Following the procedure of Example 25 (a) except for using pin-4-acetic acid, the title compound (0 .014 g, 40%) was prepared: MS (ES) m / e 460.4 (M + H).⁺. Elemental analysis: C₂₇H₂₉N_ThreeO_Four・ CF_ThreeCO_TwoH ・ 2H_TwoCalculated value (%) as O; C, H, 5.62; N, 6.89; Found (%); C, 57.44; H, 5.3. 2: N, 6.87.Example 28 ( ±) -2- (Carboxymethyl) -3-oxo-8- [3- (pyridin-2-ylamino) -1- Propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Preparation of a) (±) -2- (tert-butoxycarboxymethyl) -3-oxo-8- [3- [N- (1-O Oxo-pyridin-2-yl) -N- (tert-butoxycarbonyl) amino] -1-propylthio [Xy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate   Use tert-butyl bromoacetate instead of 4-trifluoromethylbenzyl bromide The title compound (1.0 g, 80%) was prepared according to the procedure of Example 24 (a), except that Prepared: MS (ES) m / e 614.4 (M + H)⁺. b) (±) -2- (tert-butoxycarboxymethyl) -3-oxo-8- [3- [N- (pyridi 2-N-yl) -N- (tert-butoxycarbonyl) amino] -1-propyloxy] -2,3 , 4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxy) [Cicarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) )-Instead of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -2- (tert-butoxycarboxymethyl) -3-oxo-8- [3- [N- (1- Oxo-pyridin-2-yl) -N- (tert-butoxycarbonyl) amino] -1-propylthio [Xy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate But the title compound (0.72 g, 77% ) Was prepared: MS (ES) m / e 598.4 (M + H).⁺. c) (±) -2- (carboxymethyl) -3-oxo-8- [3- (pyridin-2-ylamino) -1-Proxyoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4- Methyl acetate   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Le) Amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4, Instead of 5-tetrahydro-1H-2-benzazepine-4-acetic acid, (±) -2- (tert-butyl Toxicarboxymethyl) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert -Butoxycarbonyl) amino] -1-propyloxy] -2,3,4,5-tetrahydro- Operation of Example 25 (a), except that 1H-2-benzazepine-4-methyl acetate is used The title compound (0.57 g, quant.) Was prepared according to: MS (ES) m / e 4 42.3 (M + H)⁺. d) (±) -2- (carboxymethyl) -3-oxo-8- [3- (pyridin-2-ylamino) -1-Proxyoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4- Acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, Instead of (5-tetrahydro-1H-2-benzazepine-4-ethyl acetate, (±) -2- ( Carboxymethyl) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyl Oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate Other than using, according to the procedure of Example 1 (c), the title compound (0.30 g, 56% ) Was prepared: MS (ES) m / e 428.4 (M + H).⁺. Elemental analysis: C_{twenty two}H_{twenty five}N_ThreeO₆・ 2H_TwoCalculated as O (%); C, 57.01; H, 6.31; N, 9.07; Found (%); C, 57.27; H, 6.24; N, 8.86.                                Example 29 ( ±) -2- (4-Aminobenzyl) -3-oxo-8- [3- (pyridin-2-ylamino) -1 -Propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Preparation of a) (±) -2- (4-Nitrobenzyl) -3-oxo-8- [3- [N- (1-oxopyridine- 2-yl) -N- (tert-butoxycarbonyl) amino] -1-propyloxy] -2,3,4 , 5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   Use 4-nitrobenzyl bromide instead of 4-trifluoromethylbenzyl bromide But following the procedure of Example 24 (a), but with the title compound (0.284 g, 69% ) Prepared: MS (ES) m / e 635.3 (M + H)⁺. b) (±) -2- (4-aminobenzyl) -3-oxo-8- [3- [N- (1-oxopyridine- 2-yl) -N- (tert-butoxycarbonyl) amino] -1-propyloxy] -2,3,4 , 5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxy) [Cicarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) )-Instead of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -2- (4-nitrobenzyl) -3-oxo-8- [3- [N- (1-oxopyridine- 2-yl) -N- (tert-butoxycarbonyl) amino] -1-propyloxy] -2,3,4 Performed except using methyl 5,5-tetrahydro-1H-2-benzazepine-4-acetate Following the procedure of Example 24 (b), the title compound (0.104 g, 40%) was prepared. : MS (ES) m / e 589.3 (M + H)⁺. c) (±) -2- (4-aminobenzyl) -3-oxo-8- [3- [N- (pyridin-2-yl)- N- (tert-butoxycarbonyl) amino] -1-propyloxy] -2,3,4,5-tetra Lahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, Instead of (5-tetrahydro-1H-2-benzazepine-4-ethyl acetate, (±) -2- ( 4-aminobenzyl) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- ( tert-butoxycarbonyl) amino] -1-propyloxy] -2,3,4,5-tetrahi Example 1 (c) except that dro-1H-2-benzazepine-4-methyl acetate was used. Following the procedure, the title compound (0.08 g, 79%) was prepared: MS (ES) m / E 575.4 (M + H)⁺. d) (±) -2- (4-aminobenzyl) -3-oxo-8- [3- (pyridin-2-ylamino ) -1-Propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4- Acetic acid   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Le) Amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4, Instead of 5-tetrahydro-1H-2-benzazepine-4-acetic acid, (±) -2- (4-amido) Nobenzyl) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxyca) Rubonyl) amino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-be The title was prepared according to the procedure of Example 25 (a) except that ndazepine-4-acetic acid was used. Compound (0.029 g, 44%) was prepared: MS (ES) m / e 475.4 (M + H)⁺. Elemental analysis: C₂₇H₃₀N_FourO_Four・ 2CF_ThreeCO_TwoH 1.5H_TwoO Calculated value (%); C, 51.03; H, 4.83; N, 7.68; Measured value (%); C, 50. 92; H, 4.78; N, 7.64.                                Example 30 ( ±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (benzoyl) amino] -1- Propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahi Preparation of Dro-1H-2-benzazepine-4-acetic acid a) (±) -3-oxo-8- [3- (1-oxopyridin-2-yl) amino-1-propyl Oxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H -2-Benzazepine-4-methyl acetate   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, (±) -3-oxo instead of 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid So-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarbonyl) a Mino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5- Example 2 except that tetrahydro-1H-2-benzazepine-4-methyl acetate was used. The title compound (1.9 g, 90%) was prepared according to the procedure of 5 (a): MS ( ES) m / e 558.3 (M + H)⁺. b) (±) -3-oxo-8- [3- (pyridin-2-yl) amino-1-propyloxy] -2 -(4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benz A Zepin-4-methyl acetate   (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxy) [Cicarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) )-Instead of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -3-oxo-8- [3- (1-oxopyridin-2-yl) amino-1-propyl Oxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H Following the procedure of Example 24 (b) except that methyl 2-benzazepine-4-acetate was used. Thus, the title compound (0.40 g, 88%) was prepared: MS (ES) m / e 54 2.3 (M + H)⁺. c) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (benzoyl) amino]- 1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetra Hydro-1H-2-benzazepine-4-methyl acetate   Benzoyl chloride (0.094 mL, 0.8 mmol) was added to (±) -3-oxo-8- [ 3- (pyridin-2-yl) amino-1-propyloxy] -2- (4-trifluoromethyl Benzyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (0.4 g, 0.74 mmol) and diisopropylethylamine (0.5 mL) 2.9 mmol) in dichloromethane (10 mL). 18 hours Thereafter, the solution was concentrated and the residue was chromatographed on silica gel (1: 1 ethyl acetate). / Hexane) to give the title compound (0.293 g, 61%): MS (ES ) M / e 646.2 (M + H)⁺. d) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (benzoyl) amino]- 1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetra Hydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -3-O instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate Oxo-8- [3- [N- (pyridin-2-yl) -N- (benzoyl) amino] -1-propylthio [Xy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H- 2-benz A crude standard was prepared according to the procedure of Example 1 (c) except that azepine-4-methyl acetate was used. The title compound was prepared. ODS chromatography (10-80% acetonitrile / Water (containing 0.1% TFA) for more than 1 hour), concentrate and freeze-dry This gave the title compound (0.025 g, 10%): MS (ES) m / e 632. 4 (M + H)⁺. Elemental analysis: C₃₅H₃₂F_ThreeN_ThreeO_Five・ 0.85CF_ThreeCO_TwoCalculate as H C, 60.50; H, 4.54; N, 5.74; Found (%); C, 60.22 H, 4.35; N, 5.77.                                Example 31 ( ±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butylacetyl) a Mino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5- Preparation of tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butyl) Ruacetyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate   Tert-butyl acetate (0.228 mL, 1.2 mmol) in dichloromethane (10 oxalyl chloride (1 mL, 11.4 mmol) followed by D Reacted with MF (0.0005 mL, 0.06 mmol). The reaction was left at room temperature for 1. Stir for 5 hours and then concentrate. Dissolve the residue in dichloromethane (5 mL), ±) -3-oxo-8- [3- (1-oxopyridin-2-yl) amino-1-propyloxy ] -2- (4-Trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-be Methyl nzazepine-4-acetate (0.35 g, 0.6 mmol) and triethyl acetate To a solution of min (0.5 mL, 2.4 mmol) in dichloromethane (10 mL) did. After 18 hours, the solution was washed with water (1 ×), 5% sodium bicarbonate (2 ×), water (1 ×), 5% citric acid (2 ×), water (1 ×) and saturated sodium chloride (1 ×) ). The organic layer was concentrated to give the title compound (0.4 g, 97% ): MS (ES) m / e 656.4 (M + H)⁺. b) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butylacetyl) ) Amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4, Methyl 5-tetrahydro-1H-2-benzazepine-4-acetate   (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxy) Cicarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl ) Instead of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butyl) [Acetyl] amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl)- Methyl 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate The title compound (0.22 g, 56%) was prepared according to the procedure of Example 24 (b). Prepared: MS (ES) m / e 642.3 (M + H)⁺. c) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butylacetyl) ) Amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4, 5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -3-O instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate Oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butylacetyl) amino] -1-p Ropyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahydrido B) The procedure of Example 1 (c) was repeated except that methyl 1H-2-benzazepine-4-methyl acetate was used. The crude title compound was prepared according to the crop. ODS chromatography (10-8 (0% acetonitrile / water (containing 0.1% TFA) for 1 hour or more). , Concentrated and lyophilized to give the title compound (0.022 g, 10%): MS (E S) m / e 626.4 (M + H)⁺. Elemental analysis: C₃₄H₃₈F_ThreeN_ThreeO_Five・ H_TwoO Calculated value (%); C, 63.44; H, 6.26; N, 6.53; measured value (%); H, 5.96; N, 6.39.                                Example 32 ( ±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (isobutoxycarbonyl) Amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4, Preparation of 5-tetrahydro-1H-2-benzazepine-4-acetic acid a) (±) -3-oxo-8- [3- [N- (1-oxo-pyridin-2-yl) -N- (isobutene) [Oxycarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylben (Jill) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate   Example 30 (except using isobutyl chloroformate instead of benzoyl chloride) Following the procedure in c), the title compound (0.47 g, 80%) was prepared: MS (E S) m / e 658.3 (M + H)⁺. b) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (isobutoxycarbo) Nyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3 , 4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxy) [Cicarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) )-Instead of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -3-oxo-8- [3- [N- (1-oxo-pyridin-2-yl) -N- (isobut [Oxycarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylben (Jil) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate But following the procedure of Example 24 (b), but with the title compound (0.4 g, 63%) Was prepared: MS (ES) m / e 642.3 (M + H).⁺. c) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (isobutoxycarbo) Nyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3 , 4,5-Tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, (±) -3-O instead of 5-tetrahydro-1H-2-benzazepine-4-ethyl acetate Oxo-8- [3- [N- (pyridin-2-yl) -N- (isobutoxycarbonyl) amino] -1 -P Ropyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahydrido B) The procedure of Example 1 (c) was repeated except that methyl 1H-2-benzazepine-4-methyl acetate was used. The crude title compound was prepared according to the crop. ODS chromatography (10-8 (0% acetonitrile / water (containing 0.1% TFA) for 1 hour or more). , Concentrated and lyophilized to give the title compound (0.008 g, 20%): MS (E S) m / e 628.3 (M + H)⁺. Elemental analysis: C₃₃H₃₆F_ThreeN_ThreeO₆・ 0.25C F_ThreeCO_TwoH ・ 0.5H_TwoCalculated value (%) as O; C, 60.49; H, 5.64; N , 6.32; found (%); C, 60.78; H, 5.50; N, 6.28.                                Example 33 ( S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- (4 -Trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benzaze Preparation of pin-4-acetic acid a) (S) -3-Oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-but [Xycarbonyl) amino] -1-propyloxy] -2,3,4,5-tetrahydro-1H- 2-benzazepine-4-methyl acetate   (±) -8-Hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benza (S) -8-Hydroxy-3-oxo-2,3,4,5- instead of methyl zepin-4-acetate Example 1 except that tetrahydro-1H-2-benzazepine-4-methyl acetate was used. Following the procedure in (a), the title compound (3.0 g, 83%) was prepared: MS (E S) m / e 50.3 (M + H)⁺. b) (S) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-but [Oxycarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylben (Jill) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate   (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxy) [Cicarbonyl) amino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2 (S) -3-Oxo-8- [3- [N- (1-O-methyl-benzazepine-4-methylacetate) Kisopi Lysin-2-yl) -N- (tert-butoxycarbonyl) amino] -1-propyloxy]- Methyl 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate And the title compound (2.3 g, 72%) was prepared according to the procedure of Example 24 (a). Done: MS (ES) m / e 658.2 (M + H)⁺. c) (S) -3-Oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbo) Nyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3 , 4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxy) [Cicarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) )-Instead of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (S) -3-Oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-but [Oxycarbonyl) amino] -1-propyloxy] -2- (4-trifluoromethylben (Jil) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate The title compound (1.1 g, 50%) was prepared according to the procedure of Example 24 (b), except that Was prepared: MS (ES) m / e 642.1 (M + H).⁺. d) (S) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbo) Nyl) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3 , 4,5-Tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, (S) -3 instead of methyl 4,5-tetrahydro-1H-2-benzazepine-4-acetate -Oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbonyl) amino ] -1-Propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetra Example 24 (except using lahydro-1H-2-benzazepine-4-methyl acetate) The title compound (0.8 g, 60%) was prepared according to the procedure of c): MS (ES ) M / e 628.1 (M + H)⁺. e) (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2 -(4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benz Azepine-4-acetic acid   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, Instead of 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid, (S) -3-oxo So-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarbonyl) amino] -1- Propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahi The procedure of Example 25 (a), except that dro-1H-2-benzazepine-4-acetic acid was used. To give the crude title compound. ODS chromatography (30% Purify by concentrating on tonitrile / water (containing 0.1% TFA) for more than 1 hour, concentrate, freeze Drying to give the title compound (0.657 g, 72%): [α]_D−42 ° (c1. MS, (ES) m / e 528.1 (M + H)⁺. Elemental analysis: C₂₈ H₂₈F_ThreeN_ThreeO_Four・ 2CF_ThreeCO_TwoH ・ 3.75H_TwoCalculated value (%) as O; C, 46 .69; H, 4.59; N, 5.10; found (%); C, 46.47; H, 4.58; N, 5.48.                                Example 34 ( ±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2,3, Preparation of methyl 4,5-tetrahydro-1H-2-benzazepine-4-acetate a) (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2 , 3,4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate   The procedure of Example 1 (b), except that isopropanol was used instead of ethanol. The title compound (0.35 g, 76%) was prepared according to: MS (ES) m / e 384.4 (M + H)⁺.                                Example 35 ( S) -3-Oxo-8- [3- (1,4,5,6-tetrahydropyrimid-2-ylamino)- 1- Propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetra Preparation of hydro-1H-2-benzazepine-4-acetic acid a) (S) -8- [3- (4-nitrobenzyloxycarbonylamino) -1-propylthio [Xy] -3-oxo-2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetra Hydro-1H-2-benzazepine-4-methyl acetate   (S) -8-hydroxy-3-oxo-2- [4- (trifluoromethyl) benzyl] -2, Methyl 3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.14 g, 0.1 .34 mmol) and Ph_ThreeP (0.13 g, 0.50 mmol) in dichloromethane (2 mL) at 0 ° C. was added to 3- (4-nitrobenzyloxycarbonylamido). C-1-propanol (0.13 g, 0.51 mmol) and azodicarboxylic acid die A solution of chill (0.08 mL, 0.50 mmol) was added dropwise. Remove the ice bath at the end of the addition. The reaction was stirred at room temperature. After 18 hours, the solvent was removed and the product Flash chromatography on gel (100% chloroform to 5% meta (Nol / chloroform) to give the title compound (0.12 g) as a colorless oil. .b) (S) -8- (3-Amino-1-propyloxy) -3-oxo-2- [4- (trifluoro Methyl) benzyl] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Methyl   (S) -8- [3- (4-nitrobenzyloxycarbonylamino) -1-propyloxy [S] -3-oxo-2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahi Draw 1H-2-Methyl benzazepine-4-acetate (0.12 g, 0.19 mmol) To a solution in methanol (2 mL) was added 10% Pd / C (20 mg). Reaction volume The vessel was flushed with hydrogen, and then a hydrogen-filled balloon was attached. After 4.5 hours Drains hydrogen The catalyst was removed by filtration through Celite. Remove solvent and label The compound (0.09 g) was obtained as a pale yellow residue. Do not purify this material further Used well. MS (ES) m / e 465.3 (M + H)⁺. c) (S) -3-Oxo-8- [3- (pyrimidin-2-ylamiha-1-propyloxy]- 2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2-be Nzezepine-4-methyl acetate   (S) -8- (3-amino-1-propyloxy) -3-oxo-2- [4- (trifluoromethyl Tyl) benzyl] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Chill (0.09 g, 0.19 mmol), 2-bromopyrimidine (0.09 g, 0.19 mmol) 57 mmol) and diisopropylamine (0.17 mL, 0.98 mmol) Of DMF (2 mL) was heated at 80 ° C. for 18 hours. Cool the reaction to room temperature And concentrated to give a yellow residue. Flash chromatography on silica gel (2 % Methanol / ethyl acetate) to give the title compound (42 mg) as a colorless oil As obtained. MS (ES) m / e 543.1 (M + H)⁺. d) (S) -3-oxo-8- [3- (3,4,5,6-tetrahydropyrimid-2-ylamido) D) -1-Propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5- Methyl tetrahydro-1H-2-benzazepine-4-acetate   (S) -3-Oxo-8- [3- (pyrimidin-2-ylamino) -1-pro Pyroxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydr B-1H-2-Methyl benzazepine-4-acetate (42 mg, 0.08 mmol), ice Acetic acid (2 mL), concentrated hydrochloric acid (0.2 mL) and 10% Pd / C (10 mg) Was. The mixture was shaken under hydrogen (40 psi) for 5 hours, then evacuated of hydrogen, The catalyst was removed by filtration through Celite. Evaporate solvent and mark as dark residue The compound (52 mg) was obtained. This was used without further purification. MS (E S) m / e 547.2 (M + H)⁺. e) (S) -3-oxo-8- [3- (3,4,5,6-tetrahydropyrimid-2-ylamido) D) -1-Propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5- Tetrahydro-1H-2-benzazepine-4-acetic acid   Crude (S) -3-oxo-8- [3- (3,4,5,6-tetrahyi from Example 35 (d) Dropylopimid-2-ylamino) -1-propyloxy] -2- [4- (trifluoromethyl Benzyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester Solution in ethanol (1 mL) was added 1N sodium hydroxide (0.25 mL, 0.2 mL). 25 mmol) was added. After stirring at room temperature for 8.5 hours, 1N hydrochloric acid (0.25m (L, 0.25 mmol) was added to quench the reaction. Remove the solvent A pale yellow solid was obtained. Preparative reverse phase HPLC (Hamilton PRP-1 (registered trademark) , 30% acetonitrile / water (containing 0.1% TFA)) to give the title compound (1 8.1 mg) as a white powder. MS (ES) m / e 533.3 (M + H)⁺ . Elemental analysis: C₂₇H₃₁N_FourF_ThreeO_Four・ 2H_TwoO ・ 2CF_ThreeCO_TwoAs H, the calculated value (% C, 46.74; H, 4.68; N, 7.03; Measurement (%); C, 46.34; H , 4.31; N, 6.82.                                Example 36 ( ±) -3-oxo-8- [3- (N- (pyridin-2-yl) -N- (methyl) amino) -1-pro Pyroxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydr B-1 Preparation of 1H-2-benzazepine-4-acetic acid a) (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (methyl) a Mino)]-1-propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4, 5-tetrahydro-1H-2-benzazepine-4-acetic acid   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, (±) -3-oxo instead of 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid So-8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarbonyl) a Mino] -1- Propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahi Example 25 (a), except that methyl dro-1H-2-benzazepine-4-methyl acetate was used. The hydrochloride was prepared according to the procedure described in. Ethyl acetate and 5% sodium bicarbonate This material was converted to the free base by partitioning between. Separate the ethyl acetate layer, Concentration gave the title compound (4.1 g, 100%). MS (ES) m / e 558 .3 (M + H)⁺. b) (±) -3-oxo-8- [3- (N- (1-oxopyridin-2-yl) -N-methylamido D) -1-Propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5- Methyl tetrahydro-1H-2-benzazepine-4-acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -3-oxo-8- [3- [N- (1-oxopyridin-2-yl) -N- (methyl) ami G)]-1-Propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5 Example 26 (a) except that -tetrahydro-1H-2-benzazepine-4-acetic acid was used. The title compound (3.0 g, 94%) was prepared according to the procedure of MS) (MS). m / e 572.3 (M + H)⁺. c) (±) -3-oxo-8- [3- (N- (pyridin-2-yl) -N- (methyl) amino) -1- Propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetra Hydro-1H-2-benzazepine-4-methyl acetate   (±) -8- [3- [2- (N-oxopyridyl) amino] -1-propyloxy] -2-methyl 3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester (±) -3-oxo-8- [3- (N- (1-oxopyridin-2-yl) -N- (me Tyl) amino) -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3 Except that methyl 4,4,5-tetrahydro-1H-2-benzazepine-4-acetate was used. Following the procedure of Example 4 (b), the title compound (0.32 g, 60%) was prepared: MS (ES) m / e 556.2 (M + H)⁺. d) (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (methyl) amino]]-1- Propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetra Hydro-1H-2-benzazepine-4-acetic acid   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -2-methyl-3-oxo Instead of methyl 2,3,4,5-tetrahydro-1H-2-benzazepine-4-methyl acetate (±) -3-oxo-8- [3- (N- (pyridin-2-yl) -N- (methyl) amino) -1-pro Pyroxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro- Except for using 1H-2-benzazepine-4-methyl acetate, the procedure of Example 4 (c) was repeated. Therefore, the title compound (0.02 g, 15%) was prepared: MS (ES) m / e 5 42.1 (M + H)⁺. Elemental analysis: C₂₉H₃₀N_ThreeO_FourF_Three・ CF_ThreeCO_TwoH ・ H_TwoO Calculated value (%); C, 55.28; H, 4.94; N, 6.24; measured value (%); H, 4.68; N, 6.14.                                Example 37 ( S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- (2 , 2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepi Preparation of N-4-acetic acid a) (S) -3-Oxo-8- [3- (1-oxopyridin-2-ylamino) -1-propyl Oxy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H- 2-benzazepine-4-methyl acetate   (S) -8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H- Methyl 2-benzazepine-4-acetate (19 g, 57.4 mmol) in dry THF ( 400 mL) and dry DMF (200 mL) in a stirred solution under argon. 2- (3-hydroxypropylamihapyridine N-oxide (11.6 g, 69 mm Mol) and triphenylphosphine (18.0 g, 69 mmol). After all solids were completely dissolved (after ３０30 minutes), the reaction was cooled to 0 ° C. in an ice bath, Diisopropyl azodicarboxylate (14.3 mL, 69 mmol) was syringed. Was added via The reaction was slowly warmed to room temperature and stirred for 18 hours. Concentrate on silica gel Flash chromatography (8: 2: 1 chloroform / ethyl acetate / ethanol) To give the title compound (20.83 g, 75%) as a solid foam. By recycling the starting material recovered from the above reaction, 5.73 g of fresh The product was obtained and a total of 26.56 g (96%) of the title compound could be obtained: MS ( ES) m / e 482.2 (M + H)⁺. b) (S) -3-oxo-8- [3- (pyridin-2-ylamiha-1-propyloxy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-methyl acetate   (S) -3-oxo-8- [3- (1-oxopyridin-2-ylamino) -1-propylthio [Xy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2- Isopropano of methyl benzazepine-4-acetate (26.56 g, 55 mmol) To a stirred solution in urea (500 mL) was added 10% palladium on activated carbon (8 g, 7.5 mm Mol, carefully pre-wetted in isopropanol under argon) was added . The reaction was then heated to reflux in an oil bath set at 90 ° C. under argon. 6 After hours, a new amount of 10% palladium on activated carbon (8 g, 7.5 mmol, algo Under care, pre-wetted with isopropanol) and cyclohexene ( 55.7 mL, 550 mmol) were added. After a further 18 hours, the reaction was After hot filtration through celite, the filter bed was separated from methanol / chloroform (1: 1) (4 00 mL). The filtrate is concentrated under reduced pressure and the residue is flashed on silica gel. Purification by column chromatography (95: 5 chloroform / methanol) The title compound (19.50 g, 76%) was obtained as a crystalline foam: TLC (silica, 5% methanol in chloroform) R_f 0.52; MS (ES) m / e 466.3 (M + H)⁺. c) (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2 -(2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-acetic acid   (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzaze Pin-4-methyl acetate (19.50 g, 42 mmol) in dioxane (150 mL) Add aqueous 1N sodium hydroxide (75 mL, 75 mmol) to the stirred solution in did. The cloudy reaction was stirred at room temperature for 2 hours, then the resulting homogeneous solution was added to aqueous 1 Neutralized with N hydrochloric acid (75 mL, 75 mmol). The solution is rotary evaporated The product was concentrated to almost a dry state by a filter and the product was precipitated. Decant the supernatant And the remaining gummy solid was redissolved in methanol. Then, its colorless dissolution The solution was concentrated again on a rotary evaporator. Triturate the remaining solid with a small amount of water. , Filtered and dried under vacuum to give the title compound (16. (38 g, 86%). HPLC (Hamilton PRP-1 (registered trademark), 25 % Acetonitrile / water (containing 0.1% TFA) k '= 3.1; [α]_D-112.3 ° (c, 1.0, methanol); MS (ES) m / e 452.3 (M + H).⁺. Elemental analysis: C_{twenty two}H_{twenty four}F_ThreeN_ThreeO_FourCalculated value (%); C, 58.53; H, 5.3 6; N, 9.31; found (%); C, 58.37; H, 5.42; N, 9.20.Example 38 ( R) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- (2 , 2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepi Preparation of N-4-acetic acid a) (R) -3-oxo-8- [3- (1-oxopyridin-2-ylamiha-1-propylthio) [Xy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2- Benzazepine-4-methyl acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide (0.33 g , 2 mmol) and diethyl azodicarboxylate (0.3 mL, 2 mmol) The solution in anhydrous DMF (10 mL) was added to (R) -8-hydroxy-3-oxo-2- (2,2, 2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine- 4-Methyl acetate (0.3 g, 1 mmol) and triphenylphosphine (0.4 (85 g, 26 mmol) in anhydrous dichloromethane (10 mL) at room temperature. It was dripped slowly. After 17 hours, the reaction was concentrated. Silica gel chromatograph (Gradient: 0.5% -5% methanol / dichloromethane) to give a colorless oil. The title compound (0.35 g, 80%) was obtained: MS (ES) m / e 482.3 (M + H)⁺. b) (R) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2 -(2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-methyl acetate   (R) -3-oxo-8- [3- (1-oxopyridin-2-ylamino) -1-propylthio [Xy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2- Methyl benzazepine-4-acetate (0.35 g, 0.7 mmol), cyclohexene (0.75 mL, 7 mmol), 10% Pd / C (88 mg, 0.07 mmol) and And a mixture of isopropanol (9 mL) was heated to reflux under argon. 18:00 After a period of time, fresh 10% Pd / C (36 mg, 0.03 mmol) and cyclohexane were added. Xen (0.75 mL, 7 mmol) was added. After 36 hours, remove the reaction Heat filtration through Upon filtration, the filter bed was washed with hot ethyl acetate. Concentration gave a yellow oil. silica Gel chromatography (1% -5% methanol in dichloromethane) The title compound (0.26 g, 77%) was obtained as a colored oil: MS (ES) m / e 466. 2 (M + H)⁺. c) (R) -3-oxo-8- [3- (pyridin-2-ylamiha-1-propyloxy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-acetic acid   LiOH ・ H_TwoO (25 mg, 0.6 mmol) was added to (R) -8- [3- (2-pyridyl) Amino) -1-propyloxy] -3-oxo-2- (2,2,2-trifluoroethyl) -2 , 3,4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate (0.25 g, (0.54 mmol) in THF (5 mL) and water (2 mL) at room temperature. Was added. After 18 hours, the reaction was concentrated to dryness and the residue was dissolved in water (4 mL) did. The solution was carefully brought to a pH of about 4 with 3.0N hydrochloric acid. Collect sediment, high true Dry at 40-45 ° C under air to give the title compound (0.15 g, 62 %): MS (ES) m / e 452.1 (M + H).⁺. Elemental analysis: C_{twenty two}H_{twenty four}F_ThreeN_ThreeO_Four・ 0.5H_TwoCalculated value (%) as O; C, 57.3 8; H, 5.47; N, 9.12; measured value (%); C, 57.72; H, 5.24; 8.92.                                Example 39 ( S) -8- [3- (4-Methylpyridin-2-ylamino) -1-propyloxy] -3-oxo So-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-be Preparation of Ndazepine-4-acetic acid a) (S) -8- [3- (4-Methyl-1-oxopyridin-2-ylamino) -1-propyl Oxy] -3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahi Dro-1H-2-benzazepine-4-methyl acetate   2-[(3-hydroxy-1-propyl) amino] -4-methylpyridine-N-oxide ( 0. 60 g, 3.6 mmol) and diethyl azodicarboxylate (0.6 mL, 3.6 ml). Solution in anhydrous dichloromethane (12 mL) was added to (S) -8-hydroxy-3- Oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2 -Benzazepine-4-methyl acetate (0.60 g, 1.8 mmol) and trife Nylphosphine (0.95 g, 3.6 mmol) in anhydrous dichloromethane (6 mL) The solution was added dropwise at room temperature over 3-4 minutes. After 17 hours, the reaction was concentrated Was. Silica gel chromatography (gradient: 1% -5% methanol / dichloromethane) Tan) to give the title compound (0.45 g, 49%) as an off-white foam: MS (ES) m / e 496.3 (M + H)⁺. b) (S) -8- [3- (4-Methylpyridin-2-ylamino) -1-propyloxy] -3- Oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2 -Benzazepine-4-methyl acetate   (S) -8- [3- (4-Methyl-1-oxopyridin-2-ylamino) -1-propylthio [Xy] -3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydrido (B) Methyl 1H-2-benzazepine-4-acetate (0.45 g, 0.9 mmol); Clohexene (0.93 mL, 9 mmol), 10% Pd / C (0.2 g, 0.18 (Mmol) and isopropanol (9 mL) heated to reflux under argon did. After 18 hours, fresh 10% Pd / C (0.2 g, 0.18 mmol) and And cyclohexene (0.27 mL, 2.65 mmol) was added. 36 hours later, The reaction was subjected to hot filtration through celite and the filter bed was washed with hot ethyl acetate. Dark Reduction gave a yellow oil. Silica gel chromatography (1% in dichloromethane -3% methanol) to give the title compound as a white foam (0.32 g, 74%). Obtained: MS (ES) m / e 480.2 (M + H).⁺. c) (S) -8- [3- (4-Methylpyridin-2-ylamino) -1-propyloxy] -3- Oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2 -Benzazepine-4-acetic acid   LiOH ・ H_TwoO (33 mg, 0.79 mmol) was added to (S) -8- [3- (4-methyl Pyridin-2-ylamino) -1-propyloxy] -3-oxo-2- (2,2,2-trif (Fluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Chill (0.32 g, 0.67 mmol) in THF (5 mL) and water (2 mL) Added to the solution at room temperature. After 18 hours, the reaction was concentrated to dryness and the residue was washed with water ( 4 mL). The solution was extracted with ethyl acetate and carefully cautiously with 3.0N hydrochloric acid. A pH of 5 was reached. Collect the precipitate and dry under high vacuum at 40-45 ° C. to give an off-white solid To give the title compound (0.22 g, 71%): MS (ES) m / e 466. 1 (M + H)⁺. Elemental analysis: C_{twenty three}H₂₆F_ThreeN_ThreeO_FourCalculated value (%); C, 59. 35; H, 5.63; N, 9.03; found (%); C, 58.97; H, 5.55; N , 8.73.                                 Example 40 ( S) -8- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo- 2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benz Preparation of azepine-4-acetic acid a) (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo So-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-be Nzezepine-4-methyl acetate   Instead of 2-[(3-hydroxy-1-propyl) amino] pyridine N-oxide, 6- (Methylamino) -2-pyridylethanol is converted to (R) -8-hydroxy-3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benza (S) -8-Hydroxy-3-oxo-2- (2,2, 2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine- The title compound was prepared according to the method of Example 37 (a) except for using 4-acetic acid ester. Was prepared as a colorless oil: MS (ES) m / e 466.2 (M + H).⁺. b) (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo So-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-be Lens Azepine-4-acetic acid   (R) -8- [3- (2-pyridylamino) -1-propyloxy] -3-oxo-2- (2,2 , 2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine- (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1 in place of methyl 4-acetate -Ethoxy] -3-oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetra Example 37 (c) except using methyl hydro-1H-2-benzazepine-4-acetate The title compound was prepared as a white solid according to the method of MS): MS (ES) m / e  452.2 (M + H)⁺. Elemental analysis: C_{twenty two}H_{twenty four}F_ThreeN_ThreeO_Four・ 0.7H_TwoO Calculated value (%); C, 56.94; H, 5.52; N, 9.05; Measured value (%); C, 56. 80; H, 5.19; N, 8.85.                                Example 41 ( S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- (2 -Phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Preparation of a) (S) -3-Oxo-8- [3- (1-oxopyridin-2-ylamino) -1-propyl Oxy] -2- (2-phenylethyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-methyl acetate   2-[(3-hydroxy-1-propyl) amino] pyridine-N-oxide (336 mg 2.0 mmol) and diethyl azodicarboxylate (0.3 mL, 2.0 mmol) ) In anhydrous DMF (10 mL) was added to (S) -8-hydroxy-3-oxo-2- (2- (Phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid Methyl (350 mg, 1.0 mmol) and triphenylphosphine (525 mg, 2.0 mmol) in anhydrous DMF (10 mL) at room temperature. . After 24 hours, the mixture was concentrated. Flash silica gel chromatography ( Gradient: Ethyl acetate (500 mL) followed by 5% methanol / chloroform) This gave the title compound (288 mg, 57%) as an orange foam: MS (ES) m / e 504 (M + H)⁺. b) (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2 -(2-Phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4- Methyl acetate   (S) -3-oxo-8- [3- (1-oxopyridin-2-ylamino) -1-propylthio [Xy] -2- (2-phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzaze Pin-4-methyl acetate (288 mg, 0.57 mmol), cyclohexene (0.6 mL, 5.8 mmol), 10% Pd / C (62 mg, 0.58 mmol) and 2% A mixture of -propanol (6 mL) was heated to reflux under argon. 31 hours have passed Thereafter, the mixture was subjected to hot filtration through a bed of celite, and the bed was filtered with hot methanol / cooling. After washing with loroform (1; 1) (200 mL), the filtrate was concentrated. Flash Ricagel chromatography (5% methanol / chloroform) followed by 2 flash chromatography (50% THF / cyclohexane) The title compound (133 mg, 48%) was obtained as an off-white foam: MS (ES) m / e  488 (M + H)⁺. c) (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2 -(2-Phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4- Acetic acid   1.0 N LiOH (0.3 mL, 0.3 mmol) was added to (S) -3-oxo-8- [3- (Pyridin-2-ylamino) -1-propyloxy] -2- (2-phenylethyl) -2,3 , 4,5-Tetrahydro-1H-2-benzazepine-4-methyl acetate (133 mg, 0 (27 mL) in THF (1.5 mL) and water (1.2 mL) at 0 ° C. Added to the solution. The mixture was warmed to room temperature over 18 hours. The mixture Was washed with ethyl ether (2 × 5 mL) and the remaining organic solvent was removed under mild vacuum. The medium was removed. Pass the aqueous layer through a 0.45 μm Acrodisk filter then at 0 ° C. Carefully acidified to pH 6 using 10% hydrochloric acid in water. Collect the precipitate and wash with water And dried at 50 ° C. under vacuum to give the title compound as a white solid (62 mg, 48%) MS: (ES) m / e 474 (M + H).⁺. Elemental analysis: C₂₈H₃₁N_ThreeO_Four・ 0.75H_TwoCalculated as O (%); C, 69.05; H, 6.75; N, 8.63; Measured value (%); C, 6 9.05; H, 6.66; N, 8.55.                                Example 42 ( S) -8- [2- [6- (Methylamino) pyridin-2-yl] ethoxy] -3-oxo-2- ( 2-phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar Preparation of acid a) (S) -8- [2- [6- (methylamino) pyridin-2-yl] ethoxy] -3-oxo- 2- (2-phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine- 4-methyl acetate   Diisopropyl azodicarboxylate (0.3 mL, 1.5 mmol) was added to (S) -8- Hydroxy-3-oxo-2- (2-phenylethyl) -2,3,4,5-tetrahydro-1 H-2-benzazepine-4-acetic acid ester (350 mg, 1.0 mmol), 6- ( Methylamino) -2-pyridylethanol (228 mg, 1.5 mmol) and Liphenylphosphine (393 mg, 1.5 mmol) in anhydrous THF (10 mL) ) Was added to the solution at 0 ° C. The mixture was warmed to room temperature for 72 hours, And concentrated. Silica gel flash chromatography (50% ethyl acetate / Hexane) followed by another flash silica gel chromatography (25% Ethyl acetate / hexane) to give the title compound as a white foam (250 mg, 51% ) Was obtained: MS (ES) m / e 488 (M + H).⁺. b) (S) -8- [2- [6- (methylamino) pyridin-2-yl] ethoxy] -3-oxo- 2- (2-phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine- 4-acetic acid   1.0N LiOH (0.62 mL, 0.62 mmol) was added to (S) -8- [2- [6- ( Methylamino) pyridin-2-yl] ethoxy] -3-oxo-2- (2-phenylethyl) Methyl-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (250m g, 0.51 mmol) in THF (2.5 mL) and water (1.9 mL) at 0 ° C. And then the reaction was stirred at room temperature for 18 hours. The mixture Thing to ethyl Wash with ether (2 x 5 mL) then remove remaining organic solvent under gentle vacuum did. The aqueous layer was passed through a 0.45 μm Acrodisk filter, and then Carefully acidified to pH 6 using% hydrochloric acid. Collect the precipitate, wash with water and vacuum Dry at 50 ° C. under the title to give the title compound (134 mg, 55%) as a white solid. : MS (ES) m / e 474 (M + H)⁺. Elemental analysis: C₂₈H₃₁N_ThreeO_Four・ 0.7 5H_TwoCalculated value (%) as O; C, 69.05; H, 6.73; N, 8.63; Measurement Value (%); C, 69.23; H, 6.59; N, 8.55.                                Example 43 ( S) -8- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo- 2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2-be Preparation of Ndazepine-4-acetic acid a) (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo So-2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2 -Benzazepine-4-methyl acetate   (S) -8-hydroxy-3-oxo-2- [4- (trifluoromethyl) benzyl] -2, Methyl 3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (350 mg, 1.0 mmol) and Ph_ThreeP (0.23 g, 0.88 mmol) in dichloromethane (2 mL) in a solution of 6- (methylamino) -2-pyridylethanol (0.13 g, (0.88 mmol) and diethyl azodicarboxylate (0.14 mL, 0.89 ml) (Mol) in dichloromethane (2 mL) was added. After 2 days at room temperature The solvent was removed under reduced pressure. Radial chromatography on silica gel (6 m m plate, 5% methanol / chloroform), and the unreacted (S) -8-hydro Xy-3-oxo-2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahi Containing the title compound together with methyl dro-1H-2-benzazepine-4-methyl acetate; A colored oil was obtained. This material is further purified by radial chromatography on silica gel (6 mm plate, 5% ethyl acetate / hexane) and purified as a colorless oil. The title compound (0.12 g) was obtained: MS (ES) m / e 542.3 (M + H).⁺. b) (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo So-2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2 -Benzazepine-4-acetic acid   (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2- Methyl benzazepine-4-acetate (0.12 g, 0.22 mmol) in ethanol ( To the solution in 2 mL) was added 1 N sodium hydroxide (0.50 mL). At room temperature After 3.5 hours, much of the solvent was removed under reduced pressure to give a white residue. This thing The material was dissolved in water and the solution was neutralized to pH 7 with 1N hydrochloric acid. Collect the resulting precipitate And dried under reduced pressure to give the title compound (28.1 mg) as a white solid: [α ]_D-74.0 ° (c 0.05, ethanol); MS (ES) m / e 528.3 (M + H)⁺. Elemental analysis: C₂₈H₂₈F_ThreeN_ThreeO_Four・ 0.5H_TwoCalculated value (%) as O; C H, 5.45; N, 7.83; Found (%); C, 62.60; H, 5.3. 5; N, 7.66.                                Example 44 Parenteral dosage unit compositions   Preparation containing the compound of Example 1 (20 mg) as a sterilized dry powder Prepare the following as follows: Dissolve 20 mg of compound in distilled water (15 mL). The solution is filtered under sterile conditions into 25 mL multi-dose ampoules and lyophilized I do. 20 mL of 5% dextrose in water for intravenous or intramuscular injection (D5W) To restore the powder. Determine the dose from the injection volume. Then Dilution is performed by adding the weighed dose unit to another volume of D5W for injection. Or a metered dose in another drug dispensing device, such as an intravenous drip Bottles or bags or other injection-infusion systems.Example 45 Oral dosage unit composition   The capsule for oral administration was prepared by adding the compound of Example 1 (50 mg) to lactose (75 m g) and mixed with magnesium stearate (5 mg) and prepared by grinding Is done. Apply the resulting powder to a screen and fill in hard gelatin capsules .                                Example 46 Oral dosage unit composition   Tablets for oral administration are sucrose (20 mg), calcium sulfate dihydrate ( 150 mg) and the compound of Example 1 (50 mg) mixed with 10% gelatin solution And granulated. Apply the wet granules to a screen, dry, Mix with starch (10 mg), talc (5 mg) and stearic acid (3 mg) Compress into tablets.   The above description fully discloses the methods of making and using the present invention. I However, the invention is not limited to the specific examples described above, All modifications are within the scope of the appended claims. Cited herein The various references, journals, patents and other publications And is hereby incorporated by reference.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 19/10 A61P 19/10 29/00 29/00 35/00 35/00 43/00 111 43/00 111 C07D 403/12 C07D 403/12 417/12 417/12 (81) Designated country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC , NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, S) D, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AU, BB, BG, BR, CA, CN, CZ, EE, GE, GH, U, ID, IL, IS, JP, KG, KP, KR, LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, TR , TT, UA, US, UZ, VN, YU (72) Inventor Keenan, Richard McCarlock United States 19355 Pennsylvania Malvern, Bass Cove No. 796 (72) Inventor Kwon, Chet United States 19406 King of Pennsylvania, United States Miller, William Henry, United States 19473 Pennsylvania, Fell Lane 333 (72) Inventor Millin, William Henry United States 19085 Pennsylvania, Prussia, Valley Forge Circle 3000, Apartment 947 (72) Vilanova, Province, Basser Circle 154

Claims (1)

[Claims]   1. Formula (I): [Where,   R¹Is R⁷Or AC_0-4Alkyl, AC_2-4Alkenyl, AC_2-4Archi Nil, AC_3-4Oxoalkenyl, AC_3-4Oxoalkynyl, AC_1-4amino Alkyl, AC_3-4Aminoalkenyl, AC_3-4Aminoalkynyl, it Is one or more R^TenOr R⁷Even if it is replaced with an available combination of Often;   A is H, C_3-6Cycloalkyl, Het or Ar;   R⁷Is -COR⁸, -COCR '_TwoR⁹, -C (S) R⁸, -S (O)_mOR ', -S (O)_mN R'R ", -PO (OR '), -PO (OR')_Two, -NO_TwoOr tetrazolyl;   R⁸Is independently -OR ', -NR'R ", -NR'SO_TwoR ', -NR'OR' Or -OCR '_TwoCO (O) R ';   R⁹Is -OR ', -CN, -S (O)_rR ', -S (O)_mNR '_Two, -C (O) R ', -C (O) NR '_TwoOr -CO_TwoR ';   R^TenIs H, halo, -OR¹¹, -CN, -NR'R¹¹, -NO_Two, -CF_Three, CF_ThreeS ( O)_r-, -CO_TwoR ', -CONR'_Two, AC_0-6Alkyl-, AC_1-6Oxoalkyl -, AC_2-6Alkenyl-, AC_2-6Alkynyl-, AC_0-6Alkyloxy-, A -C_0-6Alkylamino- or AC_0-6Alkyl-S (O)_r-   R¹¹Is R ', -C (O) R', -C (O) NR '_Two, -C (O) OR ', -S (O)_mR 'also Is -S (O)_mNR '_TwoIs;   R^TwoIsOr   W is-(CHR^g)_a-U- (CHR^g)_b-Yes:   U is absent or CO, CR^g _Two, C (= CR^g _Two), S (O)_k, O, NR^g, C R^gOR^g, CR^g(OR^k) CR^g _Two, CR^g _TwoCR^g(OR^k), C (O) CR^g _Two, CR^g _TwoC (O), CONRⁱ, NRⁱCO, OC (O), C (O) O, C (S) O, OC (S), C ( S) NR^g, NR^gC (S), S (O)_TwoNR^g, NR^gS (O)_TwoN = N, NR^gNR^g, N R^gCR^g _Two, CR^g _TwoNR^g, CR^g _TwoO, OCR^g _Two, C≡C or CR^g= CR^gIn R;   G is NR^e, S or O;   R^gIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_{0- 6} Alkyl or Ar-C_0-6Alkyl;   R^kIs R^g, -C (O) R^gOr -C (O) OR^fIs;   RⁱIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_0-6 Alkyl, Ar-C_0-6Alkyl, or halogen, CN, NR^g _Two, OR^g, SR^g, CO_TwoR^gAnd CON (R^g)_TwoSubstituted by one to three groups selected from C_1-6Alkyl;   R^fIs H, C_1-6Alkyl or Ar-C_0-6Alkyl;   R^eIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl, C_3-7Shi Chloalkyl-C_0-6Alkyl or (CH_Two)_kCO_TwoR^gIs;   R^bAnd R^cIs independently H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_{0 -6} Alkyl or C_3-6Cycloalkyl-C_0-6Alkyl, halogen, CF_Three, OR^f , S (O)_kR^f, COR^f, NO_Two, N (R^f)_Two, CO (NR^f)_Two, CH_TwoN- (R^f)_Twoso Is or R^bAnd R^cTogether, halogen, CF_Three, C_1-4Alkyl , OR^f, S (O)_kR^f, COR^f, CO_TwoR^f, OH, NO_Two, N (R^f)_Two, CO (NR^f )_Two, And CH_TwoN (R^f)_TwoEven if substituted with up to three substituents selected from A 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or Forms methylenedioxy,   Q¹, Q^Two, Q^ThreeAnd Q^FourIs independently N or C—R^yWhere Q¹ , Q^Two, Q^ThreeAnd Q^FourOnly one of them is N,   R 'is H, C_1-6Alkyl, Ar-C_0-6Alkyl or C_3-6Cycloalkyl-C_0-6 Alkyl,   R "is R ', -C (O) R' or -C (O) OR ',   R "'is H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl, or C_3-6Cycloalkyl-C_0-6Alkyl, halogen, CF_Three, OR^f, S (O)_kR^f, COR^f, NO_Two, N (R^f)_Two, CO (NR^f)_Two, CH_TwoN (R^f)_TwoAnd   R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two, -CF_Three, C F_ThreeS (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _TwoOr halo, -OR^g,- SR^g, -CN, -NR^gR ", -NO_Two, -CF_Three, R'S (O)_r-, -CO_TwoR^g, -COR^g Or -CONR^g _TwoC optionally substituted with_1-6Alkyl,   a is 0, 1 or 2;   b is 0, 1 or 2;   k is 0, 1 or 2;   m is 1 or 2,   r is 0, 1 or 2;   s is 0, 1 or 2;   u is 0 or 1;   v means 0 or 1] Or a pharmaceutically acceptable salt thereof.   2. R^TwoBut, Where Q¹, Q^TwoAnd Q^Three, Respectively, CR^yAnd Q^FourIs CR^yOr The compound according to claim 1, wherein N is 0 and u is 0.   3. R 'is H, R "is H, C_1-6Alkyl, -C (O) C_1-6Archi , -C (O) OC_1-6Alkyl, -C (O) C_0-6Alkyl-Ar or -C (O) OC_{0- 6} Alkyl-Ar, wherein W is -CH_Two-CH_Two-And R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two, -CF_Three, -CF_ThreeS (O)_r-, -CO_TwoR^g, -COR^g-CONR^g _TwoOr C_1-6The compound according to claim 2, which is alkyl.   4. R^TwoButWhere Q¹, Q^TwoAnd Q^ThreeAre each CH and u is 0 Item 7. The compound according to Item 1.   5. R 'is H, and R "is H or C_1-6Alkyl and v is 0 Oh, W is -CH_Two-CH_TwoThe compound according to claim 4, which is-.   6. R^TwoBut, Where G is NH and R^bAnd R^cAre each H. Compound.   7. W is -NR^g-(CHR^g)_b7. The compound according to claim 6, which is-.   8. R^TwoBut Where G is NH and R^bAnd R^CTogether form halogen, C F_Three, C_1-4Alkyl, OR^f, S (O)_kR^f, COR^f, CO_TwoR^f, OH, NO_Two, N (R^f)_Two, CO (NR^f)_TwoAnd CH_TwoN (R^f)_TwoUp to three substituents selected from A 5- or 6-membered aromatic or non-aromatic carbocyclic ring which may be substituted by The compound according to claim 1, which forms a heterocyclic ring or methylenedioxy.   9. R^bAnd R^cTogether form a 6-membered aromatic carbocyclic ring. A compound as described.   10. W is -CH_Two-CH_Two10. The compound according to claim 9, which is-.   11. R^bAnd R^cTogether form a 6-membered aromatic heterocyclic ring. 8. The compound according to 8.   12. W is -CH_Two-CH_TwoThe compound according to claim 11, which is-.   13. R^TwoBut R ′ is H, and R ″ is H or C_1-4Alkyl, R^gIs H Or C_1-42. The compound according to claim 1, wherein s is 0, 1 or 2. object.   14． W is -CH_Two-CH_Two14. The compound according to claim 13, which is-.   15. R¹Is H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl , C_3-6Cycloalkyl-C_0-6Alkyl, -CH_TwoCF_Three,-(CH_Two)_1-2C (O) OR ' Or-(CH_Two)_TwoOR 'where R' is H or C_1-4Claims which is alkyl 2. The compound according to 1.   16. R¹Is H, C_1-4Alkyl, Ph-C_1-4Alkyl, -CH_TwoCF_Three,-(CH_Two )_1-2C (O) OR 'or-(CH_Two)_TwoOR 'where R' is H or C_1-4Al 16. The compound according to claim 15, which is a kill.   17． R¹Is -CH_TwoCF_Three17. The compound according to claim 16, which is   18.   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -3-oxo-2,3,4, 5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (4-Amino-2-pyridylamino) -1-propyloxy] -3-oxo -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (4-Methoxy-2-pyridylamino) -1-propyloxy] -3-oxo So-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (2-Pyridylamino) -1-propyloxy] -2-methyl-3-oxo -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (2-Imidazolylamino) -1-propyloxy] -3-oxo-2,3 , 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- [2- (1,4,5,6-tetrahydropyrimidinyl) amino] -1-propyl [Xy] -3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid ;   (±) -8- [3- (6-amino-2-pyridylamino) -1-propyloxy] -3-oxo -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [2- (2-benzimidazolyl) ethoxy] -3-oxo-2,3,4,5-te Trahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [2- (4-aza-2-benzimidazolyl) ethoxy] -3-oxo-2,3, 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [2- (benzimidazol-2-yl) -1-ethoxy] -3-oxo-2, 3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (4-Aminopyridin-2-ylamino) -1-propyloxy] -2 -Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar acid;   (±) -3-oxo-8- [3- (pyrimidin-2-ylamino) -1-propyloxy]- 2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (R) -8- [3- (4-aminopyridin-2-ylamino) -1-propyloxy] -3 -Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3-[(1,4,5,6-tetrahydropyrimidin-2-yl) a Mino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine -4-acetic acid;   (S) -8- [3- (4-aminopyridin-2-ylamino) -1-propyloxy] -3- Oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benza Zepin -4-acetic acid;   (±) -8- [3- [N- (1-oxopyridin-2-yl) -N- (tert-butoxycarboni L) amino] -1-propyloxy] -3-oxo-2,3,4,5-tetrahydro-1H-2 -Benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3, 4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( 4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-acetic acid;   (±) -2-Methyl-3-oxo-8- [3- [N- (pyridin-2-yl) -N- (methyl) amido [No] -1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine- 4-acetic acid;   (±) -2-benzyl-3-oxo-8- [3- (pyridin-2-ylamino) -1-propyl Oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -2- (carboxymethyl) -3-oxo-8- [3- (pyridin-2-ylamino)- 1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar acid;   (±) -2- (4-aminobenzyl) -3-oxo-8- [3- (pyridin-2-ylamino)- 1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (benzoyl) amino] -1 -Propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4,5-tetrahi Dro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (2-Imidazolin-2-ylamino) -1-propyloxy] -2-methyl Ru-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzaze Pin-4-acetic acid;   (±) -8- [2- (2-Aminothiazol-4-yl) -1-ethoxy] -2-methyl-3-o Xo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -8- [3- (4,6-dimethylpyridin-2-ylamino) -1-propyloxy]- 2-Methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4- Acetic acid;   (±) -8- [3- (4,5,6,7-tetrahydro-1H-1,3-diazepin-2-ylua Mino) -1-propyloxy] -2-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (tert-butylacetyl) Amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4, 5-tetrahydro-1H-2-benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (isobutoxycarboni Ru) amino] -1-propyloxy] -2- (4-trifluoromethylbenzyl) -2,3,4 , 5-Tetrahydro-1H-2-benzazepine-4-acetic acid;   (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( 4-trifluoromethylbenzyl) -2,3,4,5-tetrahydro-1H-2-benza Zepin-4-acetic acid;   (±) -3-oxo-8- [3- (4-methylpyridin-2-ylamino) -1-propylthio [Xy] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2- Benzazepine-4-acetic acid;   (±) -3-oxo-8- [3- [N- (pyridin-2-yl) -N- (methyl) amino]]-1-p Propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahi Dro-1H-2-benzazepine-4-acetic acid;   (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzaze Pin-4-acetic acid;   (R) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2- ( (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-benzaze Pin-4-acetic acid;   (S) -8- [3- (4-Methylpyridin-2-ylamino) -1-propyloxy] -3-o Ki So-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-be Ndazepine-4-acetic acid;   (S) -3-oxo-8- [3- (1,4,5,6-tetrahydropyrimid-2-ylamino) -1-propyloxy] -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-te Trahydro-1H-2-benzazepine-4-acetic acid;   (S) -3-oxo-2- (2-phenylethyl) -8- [3- (pyridin-2-ylamino)- 1-propyloxy] -2,3,4,5-tetrahydro-1H-2-benzazepine-4-vinegar acid;   (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo -2- (2-Phenylethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine- 4-acetic acid;   (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-ben Zazepine-4-acetic acid; or   (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3-oxo -2- [4- (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-1H-2- Benzazepine-4-acetic acid; Or a pharmaceutically acceptable salt thereof. The compound according to claim 1, which is   19. (S) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy ] -2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2-ben 2. The compound according to claim 1, which is zazepine-4-acetic acid or a pharmaceutically acceptable salt thereof. .   20. (S) -8- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -3- Oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1H-2 2. The composition according to claim 1, which is -benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof. Compound.   21. (S) -8- [3- (4-Methylpyridin-2-ylamino) -1-propyloxy] -3-Oxo-2- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-1 2. The composition according to claim 1, which is H-2-benzazepine-4-acetic acid or a pharmaceutically acceptable salt thereof. Listed Compound.   22. A medicament comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. Composition.   23. Having the compound according to claim 1, an antitumor agent and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising:   24. 24. The pharmaceutical composition according to claim 23, wherein the antitumor agent is topotecan.   25. 24. The pharmaceutical composition according to claim 23, wherein the antitumor agent is cisplatin.   26. A compound according to claim 1, a bone resorption inhibitor and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising:   27. α_vβ_ThreeA method of treating a condition that requires receptor antagonism. A method comprising administering to a subject in need of treatment a compound of claim 1. .   28. α_vβ_FiveA method of treating a condition that requires receptor antagonism. A method comprising administering to a subject in need of treatment a compound of claim 1. .   29. Administering the compound of claim 1 to a subject in need of treatment for osteoporosis. A method for treating osteoporosis.   30. Administering the compound of claim 1 to a subject in need of angiogenesis inhibition. A method of inhibiting angiogenesis comprising:   31. 2. The method of claim 1, wherein the subject requires inhibition of tumor growth or metastasis. A method of inhibiting tumor growth or metastasis comprising administering a compound.   32. Claims for subjects in need of treatment for atherosclerosis or restenosis Atherosclerosis or restenosis comprising administering the compound of claim 1. Cure.   33. Administering the compound of claim 1 to a subject in need of treatment for inflammation. Treatment of inflammation consisting of.   34. The compound of claim 1 and an antitumor agent are combined stepwise or physically. A method for inhibiting tumor growth that is administered together.   35. The method according to claim 34, wherein the antitumor agent is topotecan.   36. The method according to claim 34, wherein the antitumor agent is cisplatin.   37. The compound of claim 1 and a bone resorption inhibitor are added stepwise or physically. A method for treating osteoporosis or inhibiting bone loss, which is administered in combination.   38. Formula (II): [Where,   R¹Is R⁷Or AC_0-4Alkyl, AC_2-4Alkenyl, AC_2-4Al Quinyl, AC_3-4Oxoalkenyl, AC_3-4Oxoalkynyl, AC_1-4Ami Noalkyl, AC_3-4Aminoalkenyl, AC_3-4Aminoalkynyl; 1 Or more R^TenOr R⁷May be replaced by an available combination of ;   A is H, C_3-6Cycloalkyl, Het or Ar;   R⁷Is -COR⁸, -COCR '_TwoR⁹, -C (S) R⁸, -S (O)_mOR ', -S (O)_mN R'R ", -PO (OR '), -PO (OR')_Two, -NO_TwoOr tetrazolyl;   R⁸Is independently -OR ', -NR'R ", -NR'SO_TwoR ', -NR'OR' Or -OCR '_TwoCO (O) R ';   R⁹Is -OR ', -CN, -S (O)_rR ', -S (O)_mNR '_Two, -C (O) R ', -C (0) NR '_TwoOr -CO_TwoR ';   R^TenIs H, halo, -OR¹¹, -CN, -NR'R¹¹, -NO_Two, -CF_Three, CF_ThreeS ( O)_r-, -CO_TwoR ', -CONR'_Two, AC_0-6Alkyl-, AC_1-6Oxoalkyl -, AC_2-6Alkenyl-, AC_2-6Alkynyl-, AC_0-6Alkyloxy-, A -C_0-6Alkylamino- or AC_0-6Alkyl-S (O)_r-   R¹¹Is R ', -C (O) R', -C (O) NR '_Two, -C (O) OR ', -S (O)_mR 'also Is -S (O)_mNR '_TwoIs;   R^TwoIs Or  W is-(CHR^g)_a-U- (CHR^g)_b-   U is absent or CO, CR^g _Two, C (= CR^g _Two), S (O)_k, O, NR^g, CR^g OR^g, CR^g(OR^k) CR^g _Two, CR^g _TwoCR^g(OR^k), C (O) CR^g _Two, CR^g _TwoC ( O), CONRⁱ, NRⁱCO, OC (O), C (O) O, C (S) O, OC (S), C (S) NR^g, NR^gC (S), S (O)_TwoNR^g, NR^gS (O)_TwoN = N, NR^gNR^g, NR^gCR^g _Two, CR^g _TwoNR^g, CR^g _TwoO, OCR^g _Two, C≡C or CR^g= CR^gso Yes;   G is NR^e, S or O;   R^gIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_{0- 6} Alkyl or Ar-C_0-6Alkyl;   R^kIs R^g, -C (O) R^gOr -C (O) OR^fIs;   RⁱIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_{0- 6} Alkyl, Ar-C_0-6Alkyl, or halogen, CN, NR^g _Two, OR^g, SR^g , CO_TwoR^gAnd CON (R^g)_TwoSubstituted by one to three groups selected from C_1-6Alkyl;   R^fIs H, C_1-6Alkyl or Ar-C_0-6Alkyl;   R^eIs H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl, C_3-7Shi Chloalkyl-C_0-6Alkyl or (CH_Two)_kCO_TwoR^gIs;   R^bAnd R^cIs independently H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_{0 -6} Alkyl or C_3-6Cycloalkyl-C_0-6Alkyl, halogen, CF_Three, OR^f , S (O)_kR^f, COR^f, NO_Two, N (R^f)_Two, CO (NR^f)_Two, CH_TwoN (R^f)_TwoIn Or R^bAnd R^cTogether, halogen, CF_Three, C_1-4Alkyl, OR^f, S (O)_kR^f, COR^f, CO_TwoR^f, OH, NO_Two, N (R^f)_Two, CO (NR^f)_Two , And CH_TwoN (R^f)_TwoMay be substituted with up to three substituents selected from A 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, Forms methylenedioxy,   Q¹, Q^Two, Q^ThreeAnd Q^FourIs independently N or C—R^yWhere Q¹ , Q^Two, Q^ThreeAnd Q^FourOnly one of them is N,   R 'is H, C_1-6Alkyl, Ar-C_0-5Alkyl or C_3-6Cycloalkyl-C_0-6 Alkyl,   R "is R ', -C (O) R' or -C (O) OR ',   R "'is H, C_1-6Alkyl, Ar-C_0-6Alkyl, Het-C_0-6Alkyl or C_3-6 Cycloalkyl-C_0-6Alkyl, halogen, CF_Three, OR^f, S (O)_kR^f, C OR^f, NO_Two, N (R^f)_Two, CO (NR^f)_Two, CH_TwoN (R^f)_TwoAnd   R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two, -CF_Three, C F_ThreeS (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _Two, Or halo, -OR^g , -SR^g, -CN, -NR^gR ", -NO_Two, -CF_Three, R'S (O)_r-, -CO_TwoR^g, -C OR^gOr -CONR^g _TwoC optionally substituted with_1-6Alkyl,   a is 0, 1 or 2;   b is 0, 1 or 2;   k is 0, 1 or 2;   m is 1 or 2,   r is 0, 1 or 2;   s is 0, 1 or 2;   u is 0 or 1;   v means 0 or 1] Or a pharmaceutically acceptable salt thereof.   39.   (±) -3-oxo-8- [3- (pyridin-2-ylamino) -1-propyloxy] -2, Methyl 3,4,5-tetrahydro-1H-2-benzazepine-4-acetate; or   (±) -8- [3- (4-Aminopyridin-2-ylamino) -1-propyloxy] -3-o Xo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-ethyl acetate;   Or a pharmaceutically acceptable salt thereof. 39. The compound of claim 38, which is   40. Formula (III): [Where,   R¹Is R⁷Or AC_0-4Alkyl, AC_2-4Alkenyl, AC_2-4Al Quinyl, AC_3-4Oxoalkenyl, AC_3-4Oxoalkynyl, AC_1-4Ami Noalkyl, AC_3-4Aminoalkenyl, AC_3-4Aminoalkynyl; 1 Or more R^TenOr R⁷May be replaced by an available combination of ;   A is H, C_3-6Cycloalkyl, Het or Ar;   R⁷Is -COR⁸, -COCR '_TwoR⁹, -C (S) R⁸, -S (O)_mOR ', -S (O)_mN R'R ", -PO (OR '), -PO (OR')_Two, -NO_TwoOr tetrazolyl;   R⁸Is independently -OR ', -NR'R ", -NR'SO_TwoR ', -NR'OR' Or -OCR '_TwoCO (O) R ';   R⁹Is -OR ', -CN, -S (O)_rR ', -S (O)_mNR '_Two, -C (O) R ', -C (O) NR '_TwoOr -CO_TwoR ';   R^TenIs H, halo, -OR¹¹, -CN, -NR'R¹¹, -NO_Two, -CF_Three, CF_ThreeS ( O)_r-, -CO_TwoR ', -CONR'_Two, AC_0-6Alkyl-, AC_1-6Oxoalkyl -, AC_2-6Alkenyl-, AC_2-6Alkynyl-, AC_0-6Alkyloxy-, A -C_0-6Alkylamino- or AC_0-6Alkyl-S (O)_r-   R¹¹Is R ', -C (O) R', -C (O) NR '_Two, -C (O) OR ', -S (O)_mR 'also Is -S (O)_mNR '_TwoIs;   W is-(CHR^g)_a-U- (CHR^g)_b-   U is absent or CO, CR^g _Two, C (= CR^g _Two), S (O)_k, O, NR^g, CR^g OR^g, CR^g(OR^k) CR^g _Two, CR^g _TwoCR^g(OR^k), C (O) CR^g _Two, CR^g _TwoC ( O), CONRⁱ, NRⁱCO, OC (O), C (O) O, C (S) O, OC (S), C (S ) NR^g, NR^gC (S), S (O)_TwoNR^g, NR^gS (O)_Two, N = N, NR^gNR^g, N R^gCR^g _Two, CR^g _TwoNR^g, CR^g _TwoO, OCR^g _Two, C≡C or CR^g= CR^gIn R;   R^gIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_0-6 Alkyl or Ar-C_0-6Alkyl;   R^kIs R^g, -C (O) R^gOr -C (O) OR^fIs;   RⁱIs H, C_1-6Alkyl, Het-C_0-6Alkyl, C_3-7Cycloalkyl-C_0-6 Alkyl, Ar-C_0-6Alkyl, or halogen, CN, NR^g _Two, OR^g, SR^g, CO_TwoR^gAnd CON (R^g)_TwoSubstituted by one to three groups selected from C_1-6Alkyl;   R^fIs H, C_1-6Alkyl or Ar-C_0-6Alkyl;   Q¹, Q^Two, Q^ThreeAnd Q^FourIs independently N or C—R^yWhere Q¹ , Q^Two, Q^ThreeAnd Q^FourOnly one of them is N,   R 'is H, C_1-6Alkyl, Ar-C_0-6Alkyl or C_3-6Cycloalkyl-C_0-6 Alkyl,   R "is R ', -C (O) R' or -C (O) OR ',   R^yIs H, halo, -OR^g, -SR^g, -CN, -NR^gR^k, -NO_Two, -CF_Three, C F_ThreeS (O)_r-, -CO_TwoR^g, -COR^gOr -CONR^g _Two, Or halo, -OR^g , -SR^g, -CN, -NR^gR ", -NO_Two, -CF_Three, R'S (O)_r-, -CO_TwoR^g, -C OR^gOr -CONR^g _TwoC optionally substituted with_1-6Alkyl,   a is 0, 1 or 2;   b is 0, 1 or 2;   m is 1 or 2,   r represents 0, 1 or 2] Or a pharmaceutically acceptable salt thereof.   41. Formula (IV):With a compound of formula (V): R^Two-L¹React with the compound of   Where R¹And R^TwoIs the same as described in the formula (I), and the reactive functional group is Protected and L¹Is OH or halo;   Thereafter, the protecting group may be removed to form a pharmaceutically acceptable salt. A process for the preparation of the described compounds of formula (I).   42. Formula (IV): Of the formula (VI): React with the compound of   Where R¹, R ', R ", W, Q¹, Q^Two, Q^ThreeAnd Q^FourIs the description of formula (I) The same, with the reactive functional group being protected;   Thereafter, the protecting group may be removed to form a pharmaceutically acceptable salt. A process for the preparation of the described compounds of formula (I).   43. Formula (IV):Of the formula (VII): React with the compound of   Where R¹, R ', R ", W, Q¹, Q^Two, Q^ThreeAnd v are the same as described in the formula (I). The reactive functional group is protected,   Thereafter, the protecting group may be removed to form a pharmaceutically acceptable salt. A process for the preparation of the described compounds of formula (I).   44. The use according to any one of claims 1 to 21 for use as a medicament. Compound.   45. α_vβ_ThreePharmaceutical for treating diseases requiring receptor antagonism Use of a compound of formula (I) according to claim 1 in the preparation of   46. α_vβ_FivePharmaceutical for treating diseases requiring receptor antagonism Use of a compound of formula (I) according to claim 1 in the preparation of   47. The formula (1) according to claim 1 in the manufacture of a medicament for treating osteoporosis. Use of the compounds of I).   48. The formula (1) according to claim 1 in the manufacture of a medicament for inhibiting angiogenesis. Use of the compounds of I).   49. Claims in the manufacture of a medicament for inhibiting tumor growth or tumor metastasis. Use of a compound of formula (I) according to 1.   50. In the manufacture of a medicament for treating atherosclerosis or restenosis Use of a compound of formula (I) according to claim 1 in a pharmaceutical composition.   51. Formula (I) according to claim 1 in the manufacture of a medicament for treating inflammation. Use of compounds.   52. Inhibitors of tumor growth for physical combination or stepwise administration Use of a compound of formula (I) according to claim 1 and an antitumor agent in the manufacture of a medicament.   53. 53. Use according to claim 52, wherein the antitumor agent is topotecan.   54. 53. The use according to claim 52, wherein the antitumor agent is cisplatin.   55. Osteoporosis treatment physician for physical combination or stepwise administration Use of a compound of formula (I) according to claim 1 and a bone resorption inhibitor in the manufacture of a medicament. for.